HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hendel, H. Articles by Zagury, J.-F. Search for Related Content PubMed PubMed Citation Articles by Hendel, H. Articles by Zagury, J.-F.

New Class I and II HLA Alleles Strongly Associated with Opposite Patterns of Progression to AIDS¹

Houria Hendel^*, Sophie Caillat-Zucman, Hélène Lebuanec^*, Mary Carrington, Steve O’Brien^§, Jean-Marie Andrieu^¶, François Schächter^*, Daniel Zagury^*, Jay Rappaport^||, Cheryl Winkler, George W. Nelson and Jean-François Zagury^1,*

^* Laboratoire de Physiologie Cellulaire, Université Pierre et Marie Curie, Paris, France; Laboratoire d’Immunologie, Hôpital Necker, Paris, France; Intramural Research Support Program, SAIC-Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702; ^§ Laboratory of Genomic Diversity, National Cancer Institute, Frederick MD 21702; ^¶ Service de Cancérologie/SIDA, Hôpital Laennec, Paris, France; and ^|| Center for Neurovirology and Neurooncology, MCP Hahnemann University of Health Sciences, Philadelphia, PA 19102.

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
The genetics of resistance to infection by HIV-1 cohort consists of 200 slow and 75 rapid progressors to AIDS corresponding to the extremes of HIV disease outcome of 20,000 Caucasians of European descent. A comprehensive analysis of HLA class I and class II genes in this highly informative cohort has identified HLA alleles associated with fast or slow progression, including several not described previously. A quantitative analysis shows an overall HLA influence independent of and equal in magnitude (for the protective effect) to the effect of the CCR5-32 mutation. Among HLA class I genes, A29 (p = 0.001) and B22 (p < 0.0001) are significantly associated with rapid progression, whereas B14 (p = 0.001) and C8 (p = 0.004) are significantly associated with nonprogression. The class I alleles B27, B57, C14 (protective), and C16, as well as B35 (susceptible), are also influential, but their effects are less robust. Influence of class II alleles was only observed for DR11. These results confirm the influence of the immune system on disease progression and may have implications on peptide-based vaccine development.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Human MHC (HLA) is a fundamental component of the immune system, but the extent of its role in the control of HIV-1 infection and disease progression remains unclear (1, 2, 3). During an infection, binding of peptides from the infectious pathogens to HLA proteins is the first step for the initiation of the host-specific immune response. This binding step is critical, because HLA acts as a filter driving the recognition of epitopes by the host immune system (4). Because of the extensive polymorphism of HLA in the population, the immune response against a pathogen will thus vary among individuals. Extensive studies of an HLA-restricted specific response to HIV ex vivo through CTL assays and in vitro through peptide-binding experiments (5, 6, 7) suggest that the presentation of selective epitopes by HLA is pivotal to the immune regulation of HIV. Indeed, the emergence of escape mutants from HIV-1-specific CTLs directed toward Env, Nef, or Gag has been correlated with disease progression (8, 9, 10).

Many cohort studies have looked for associations between HLA alleles and HIV disease progression; however, although several alleles and haplotypes have been associated with accelerated or retarded progression to AIDS, results for many alleles have been inconsistent, and a clear pattern of how HLA influences disease progression has not emerged (reviewed in Refs. 3 and 11–13). HLA presents difficult statistical problems for disease association analysis. Due to the extreme polymorphism of HLA class I and II loci, most individual alleles are relatively rare. For the important case of HLA B, 70% of Caucasian chromosomes carry alleles whose frequency is 10%; to account for 95% of the population, 19 different alleles, with frequencies as low as 0.7%, must be considered (14). Small numbers of subjects with individual alleles make associations difficult to observe, whereas the large number of alleles being considered requires a large multiple comparisons (Bonferroni) correction. Thus, there are serious problems in detecting a signal of HLA influence on disease progression through the statistical noise. The obvious solution of greatly increasing the sample size is generally impractical, primarily due to the difficulty of assembling a sufficiently large cohort of well-characterized HIV-infected volunteers, and secondarily due to the expense of thorough typing for HLA alleles.

The genetics of resistance to infection by HIV-1 (GRIV)³ cohort follows a different tactic of increasing the strength of the signal by assembling a cohort of well-characterized individuals representing the extremes of rapid progression and nonprogression. The cohort now consists of 200 slow progressors (SPs) and 75 rapid progressors (RPs). Because the definition of slow progression captures 1% of HIV-infected subjects, we are in effect looking at the extremes of a cohort of 20,000 individuals, when the largest cohort studied to date has involved <2,000 patients. The quality of the GRIV cohort using this comparative approach has been previously validated successfully on the CCR5, CCR2, and stromal cell-derived factor 1 (SDF1) genes (15, 16).

The GRIV panel allows us to identify new HLA alleles that are significantly associated with slow and fast progression patterns. Our results confirm the major role of HLA in the immune control of HIV infection, which we show to be comparable in magnitude to the protective influence of CCR5-32 (16).

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Subjects

The GRIV cohort was established in 1995 in France to generate a large collection of DNAs for genetic studies of the candidate human polymorphisms associated with rapid and slow progression to AIDS (12). To avoid the confounding effects associated with racial/ethnic differences in genetic analyses, only Caucasians of European descent were recruited from hospital AIDS units throughout France. SPs were defined as asymptomatic individuals seropositive for 8 years with a CD4 cell count of >500/mm³ in the absence of antiretroviral therapy. A seropositive test older than 8 years was necessary for inclusion in the study. RPs were defined by a CD4 count of <300/mm³ at <3 years after the last seronegative testing. Upon enrollment, each patient signed an informed consent form and donated 40 ml of blood. Blood was shipped overnight from the collection centers and immediately processed in the laboratory. PBMCs were collected, and EBV-transformed B cell lines were generated as a renewable source of genetic material. Some serum (one tube) was spared, allowing for some studies on the immune response of nonprogressors (NPs) and fast progressors (FPs) (17). The analysis of the biological parameters (cell counts, viral load, etc.) presented in a previous study (16) showed that the viral load was low among most NP subjects (in average 3.4 log) at enrollment. The viral load among FPs was 1.5 log higher, even though most of these individuals were being treated by chemotherapy at the time of enrollment (16).

HLA genotyping

HLA class I and II DNA typing was performed by hybridization with sequence-specific oligonucleotide probes following amplification of the corresponding genes in the PCR according to the 12th International Histocompatibility Workshop and Conference protocols (14). We first used a sequence-specific oligonucleotide probe typing system that detects alleles at the HLA-A, -B, and -C loci (Life Codes, Stamford, CT) and DRB1, DRB3, DRB4, and DRB5 loci (BioMérieux, Lyon, France). In a second step, subtyping was performed for selected generic class I or II alleles (A29, B17, B27, and DR11) using sequence-specific primer amplification (Dynal, Oslo, Norway).

Statistical analysis

The odds ratio (OR) as an estimate of risk and the Fisher’s exact test were used to determine the strength of the allele-specific associations in the SP vs RP groups. The OR is used to estimate risk in case-control studies in which the relative risk computation is not appropriate. An OR of <1 indicates protection, whereas an OR of >1 indicates increased risk. Bonferroni corrections were conducted by multiplying the Fisher’s exact test p values by the number of allelic comparisons. p values of <0.05 were considered significant.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Associations with disease progression

Table I presents the alleles exhibiting allelic/genotypic frequency differences between the SP and RP categories. A number of alleles were associated with nonprogression, such as B14, B27, B57, C8, and C14, whereas A29, B22, B35, C16, and DR11 favored rapid progression. The results obtained were essentially identical whether computing the allelic or genotypic frequencies in the two categories of progression. In addition, several alleles exhibited a trend toward allelic/genotypic frequency differences between the SP and RP groups, with p values ranging between 0.06 and 0.1: C2 (SPs at 7.5% vs RPs at 3.3%, p = 0.09), C4 (SPs at 10.75% vs RPs at 16.45%, p = 0.078), C6 (SPs at 8.75% vs RPs at 3.95%, p = 0.057), and DR14 (SPs at 3.23% vs RPs at 7.24%, p = 0.057). Except for B14 and B35, the frequencies found in the French control population were in between the frequencies of the SP and RP groups, providing additional support that the alleles are involved in the dichotomous SP and RP phenotypes.

To determine whether homozygosity had an effect on progression, we compared patients who were heterozygous at all four loci with patients who were homozygous at one or more loci. The frequency of homozygosity was similar between the SP and RP groups. However, the frequency of homozygotes at two or more loci was significantly increased within the RP group (p = 0.025).

Of interest, we computed whether some HLA associations would specially arise when combined with sex or specific routes of infection (homosexual, heterosexual, transfusion, and i.v. drug use): no association could be found, with the exception of DR11 and women.

Known HLA linkage disequilibrium

Some HLA alleles are known to be in linkage disequilibrium and commonly occur on the same haplotype. We found the following disequilibria to be equally represented in both the SP and RP groups: A29-C16, B8-C7, B14-C8, B27-C1, B27-C2, B35-C4, B51-C14, B57-C6, B57-DR7, and A1-B8-C7-DR3. This may explain the similar association observed for some of the A, B, and C alleles, which are in positive linkage disequilibrium (Table I). Among C alleles, only C14 had a stronger individual effect (p = 0.03) than its counterpart B51 (p = 0.57). Unlike the findings reported in other studies (11, 18), we did not observe a significant frequency difference between the two groups for the A1-B8-C7-DR3 haplotype.

DR11 allele

Because of the unusual effect of DR11 with gender on progression, we studied more carefully the patients carrying this allele. Unexpectedly, there was a complete reversal of the DR11-negative effect in the presence of DR4: the 12 subjects in the cohort who are both DR11 and DR4 were all in the SP group. If we removed patients carrying the DR4 allele, the negative effect of DR11 became stronger (p = 0.0001) between the 75% remaining RP and SP patients. Table II shows that the negative effect of DR11 occurs in both males and females of the DR4-negative population. The overall negative effect of DR11 (p = 0.0001) is comparable in amplitude with the protective effect observed with CCR5-32, because 75% of the population is DR4-negative; the DR11 allelic frequency (12%) is similar to that of CCR5-32. The removal of patients carrying the DR11 allele revealed a negative effect for A1 (p = 0.01) and a strong protective effect for A25 (p < 0.0001).

HLA associations independent of CCR5, CCR2, and SDF1 protective effects

In our previous analysis of CCR5 and CCR2 polymorphisms in the GRIV cohort, we found that the CCR5-32 allele had a predominant protective effect on disease pattern, obscuring the less influential effects of CCR2–64I and SDF1–3'A (15). We performed a similar analysis for HLA by comparing the HLA allelic distribution among wild-type individuals vs those carrying one protective allele for each of the CCR5 or CCR2 genes, separately or combined. Distinguishing wild-type and heterozygous subjects for CCR5 or CCR2 did not significantly change the frequency of distribution of the HLA alleles between the two groups. Interestingly, the only two patients in the RP group carrying the CCR5-32 mutation were DR11⁺. We could not analyze the effect of SDF1–3'A variant, because this homozygous genotype was rare. Conversely, patients in the SP group carrying HLA alleles associated with rapid progression did not show an increase in the protective CCR5-32 or CCR2–64I mutant alleles.

Table III presents the distribution of individuals carrying combinations of the most significant alleles with susceptible or protective effects. The protective HLA alleles contribute at least as much as CCR5-32 to long-term survival. Individuals carrying both susceptible and protective HLA alleles are equally likely to belong to either the SP or RP group, suggesting that the strength of the HLA protective and negative effects is approximately equal.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

Our work shows that HLA alleles are influential on slow or rapid progression, and that the strength of the protective HLA alleles is comparable with and independent of the protective effect afforded by CCR5-32, as shown in Table III. The fact that CCR5-32 and some HLA alleles have independent protective effects reflects the duality of their action on viral expansion: the first by limiting viral colonization by decreased coreceptor availability and the second by mounting an efficient immune response against HIV. Because the CCR2 and SDF-1 protective effects have been observed to be as strong as CCR5 in other cohorts (of all-stages patient) but occurring later in infection (23, 24), the weakness of these effects in the GRIV cohort (16) suggests that this cohort emphasizes early effects. Indeed, the B14 allele, unlike the other HLA protective alleles, has an increased prevalence among SPs, but no decrease among RP patients (Table I); it seems to prevent the initiation of disease progression. Moreover, this allele was not detected in the other cohorts, which confirms that the B14 effect must occur before the start of the disease process. This early influence of HLA is in line with the results of Pantaleo et al. (25). We also believe that the inclusion of 75 extremely rapid progressors defined by the stringent criteria of a CD4 T cell count within 3 years of the last seronegative HIV test increases the power to detect deleterious HLA alleles that may be missed by other studies with less sensitivity. This may be because many cohort studies have a frailty bias that tends to exclude the most rapid progressors (26).

The efficiency of the CTL response against HIV may be severely compromised by viral mutations that abrogate either peptide binding to HLA or CTL recognition of the HLA-peptide complex. The likelihood of such escape mutations occurring in an HLA peptide epitope is determined by two factors: whether mutations can occur without eliminating viral viability, and whether the HLA binding and the recognition of the epitope is eliminated by a given mutation. Conversely, presentation of an HIV epitope by a particular HLA allele will tend to be resistant to escape mutation if the epitope is in a region of the HIV genome for which detailed structure is essential for viral function, and if the peptide binding groove of the allele is tolerant of limited mutations in the peptide. In line with these ideas, the protective alleles we identified, namely B27, B14, and B57, have been shown to tolerate mutations in their epitopes, as shown B27 (27), B14 (28), B57 (29, 30). Reciprocally, the recognition by susceptibility alleles A29 and B35 has been shown to be sensitive to mutations (31, 32). The case of B35 is notable for the large number of epitopes recognized (32). It is possible that this is a consequence of the instability of its presentation, with repeated immune escape followed by a response to new epitopes.

These concepts offer important support to the existing theory that protective CTL responses are those that resist escape mutation. Following this theory, a plausible vaccine approach would involve the selection of those HIV peptides that, presented as epitopes, would have the maximum resistance to escape mutations. Those already identified as persistent epitopes associated with long-term survival, presented by HLA alleles associated with nonprogression, are obvious candidates. The case of the B14-associated epitopes is of interest, because B14 seems to favor the prevention of entry in disease progression, while not having an effect on more advanced stage patients (not detected by other all-stages patient cohorts, not decreased among RPs). However, such epitopes would not be sufficient, because a vaccine designed around them might not offer protection to individuals lacking these protective HLA alleles. For alleles that elicit a less protective response, a possible strategy would be to seek out HIV epitopes, among all those potentially presented by the allele, in which the mutations that would abrogate class I binding are most strongly constrained by viral function. To do this effectively may require a more precise ability to predict peptide binding to HLA receptors than currently exists, but advances both in empirical studies of peptide HLA binding (6, 7) and in numerical modeling of peptide binding may offer this knowledge in the near future.

Because the constraints on HIV are not sufficient to control viral infection even in individuals carrying protective alleles, it is clear that other processes are involved in the escape of HIV from immune control. The progressive loss of CD4⁺ T cells undoubtedly weakens the immune response, and may account for the failure of the CTL response against new escape mutant strains that arise late in infection. A number of HIV immunosuppressive factors have been identified; in particular, our group has shown that Tat protein can act as a potent immunosuppressive toxin (33), and disease progression correlates with the loss of anti-Tat Abs (17). Such an effect could explain the ultimate ineffectiveness of even the protective HLA alleles.

To conclude, the quality of the highly selected GRIV cohort has allowed us to identify HLA alleles with effects as influential as the CCR5-32 mutation on HIV disease progression and to identify, tentatively, a pattern determining the protective or susceptible effects of a genotype. It must be emphasized that no HLA alleles are truly protective in the very long term, and that HIV immune escape and pathogenesis involve other immune evasive and destructive factors, such as Tat, which are also potential targets for vaccine approaches (34).

	Acknowledgments

 
We thank Patricia Przednowed for kind and excellent technical assistance.

	Footnotes

 
¹ This work was funded by Association de Recherche sur le SIDA, Sidaction and by Agence Nationale de Recherche sur le SIDA. This project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number N01-C0-56000.

² Address correspondence and reprint requests to Dr. Jean-François Zagury, Laboratoire de Physiologie Cellulaire, Université Pierre et Marie Curie, 4, Place Jussieu 75005 Paris, France. E-mail address:

³ Abbreviations used in this paper: GRIV, genetics of resistance to infection by HIV-1; SP, slow progressor; RP, rapid progressor; SDF, stromal cell-derived factor; OR, odds ratio.

Received for publication February 1, 1999. Accepted for publication March 18, 1999.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Westby, M., F. Manca, A. G. Dalgleish. 1996. The role of host immune response in determining the outcome of HIV infection. Immunol. Today 17:120.[Medline]
2. Haynes, B. F., G. Pantaleo, A. Fauci. 1996. Toward an understanding of the correlates of protective immunity in HIV infection. Science 271:324.[Abstract]
3. Hill, A. V. S.. 1996. HIV and HLA: confusion or complexity?. Nat. Med. 2:395.[Medline]
4. Akolbar, P. N., B. Gulwani-Akolbar, R. Pergolizzi, R. D. Bigler, J. Silver. 1993. Influence of HLA genes on TCR V segment frequencies and expression levels in peripheral blood lymphocytes. J. Immunol. 150:2761.[Abstract]
5. Goulder, P., D. Price, M. Nowak, S. Rowland-Jones, R. Phillips, A. McMichael. 1997. Co-evolution of HIV and cytotoxic T-lymphocytes responses. Immunol. Rev. 159:17.[Medline]
6. Gaudebout, P., D. Zeliszewski, J. J. Golvano, C. Pignal, S. Le Gac, F. Borras-Cuesta, G. Sterkers. 1997. Binding analysis of 95 HIV gp120 peptides to HLA-DR1101 and -DR0401 evidenced many HLA-class II binding regions on gp120 and suggested several promiscuous regions. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 14:91.[Medline]
7. Atman, J. D., P. A. H. Moss, P. J. R. Goulder, D. H. Barouch, M. G. McHeyzer-Williams, J. I. Bell, A. J. McMichael, M. M. Davis. 1996. Phenotypic analysis of antigen-specific T lymphocytes. Science 274:94.[Abstract/Free Full Text]
8. Koenig, S., A. J. Conley, Y. A. Brewah, G. M. Jones, S. Leath, L. J. Boots, V. Davey, G. Pantaleo, J. F. Demarest, C. Carter, et al 1995. Transfer of HIV-1-specific cytotoxic T lymphocytes to an AIDS patient leads to selection for mutant HIV variants and subsequent disease progression. Nat. Med. 1:330.[Medline]
9. Borrow, P., H. Lewicki, X. Wei, M. S. Horwitz, N. Peffer, H. Meyers, J. A. Nelson, J. E. Gairin, B. H. Hahn, M. B. A. Oldstone, G. M. Shaw. 1997. Antiviral pressure exerted by HIV-1-specific CTLs during primary infection demonstrated by rapid selection of CTL escape virus. Nat. Med. 3:205.[Medline]
10. Goulder, P., R. E. Philips, R. A. Colbert, S. McAdam, G. Ogg, M. A. Nowak, P. Giangrande, G. Luzzi, B. Morgan, A. Edwards, A. J. McMichael, S. Rowland-Jones. 1997. Late escape from an immunodominant CTL response associated with progression to AIDS. Nat. Med. 3:212.[Medline]
11. Roger, M.. 1998. Influence of host genes on HIV-1 disease progression. FASEB J. 12:625.[Abstract/Free Full Text]
12. Hendel, H., Y. Y. Cho, N. Gauthier, J. Rappaport, F. Schächter, J. F. Zagury. 1996. Contribution of cohorts studies in understanding HIV pathogenesis: introduction of the GRIV cohort and preliminary results. Biomed. Pharmacother. 50:480.[Medline]
13. Malkovsky, M.. 1996. HLA and natural history of HIV infection. Lancet 348:142.[Medline]
14. D. Charron, ed. Genetic Diversity of HLA: Functional and Medical Implications 1997 EDK Publisher, Sèvres, France.
15. Rappaport, J., Y. Y. Cho, H. Hendel, E. J. Schwartz, F. Schächter, J. F. Zagury. 1997. The 32-bp CCR5 gene deletion confers resistance to fast progression among HIV-1-infected heterozygous individuals. Lancet 349:922.[Medline]
16. Hendel, H., N. Henon, H. Lebuanec, A. Lachgar, H. Poncelet, S. Caillat-Zucman, C. Winkler, M. W. Smith, L. Kenefic, S. O’Brien, et al 1998. Distinctive effects of CCR5, CCR2, and SDF1 genetic polymorphisms on AIDS progression. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 19:381.[Medline]
17. Zagury, J. F., A. Still, W. Blattner, A. Lachgar, H. Lebuanec, M. Richardson, J. Rappaport, H. Hendel, B. Bizzini, A. Gringeri, et al 1998. Antibodies to the HIV-1 Tat protein correlated with nonprogression to AIDS: a rationale for the use of Tat-toxoid as an HIV-1 vaccine. J. Hum. Virol. 1:282.[Medline]
18. Steel, C. M., C. A. Ludlam, D. Beatson, J. F. Peutherer, R. J. Cuthbert, P. Simmonds, H. Morrison, M. Jones. 1988. HLA haplotype A1 B8 DR3 as a risk factor for HIV-related disease. Lancet 1:1185.[Medline]
19. Kaslow, R. A., M. Carrington, R. Apple, L. Park, A. Munoz, A. J. Saah, J. J. Goedert, C. Winkler, S. J. O’Brien, C. Rinaldo, et al 1996. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat. Med. 2:405.[Medline]
20. Cruse, J. M., M. N. Brackin, R. E. Lewis, W. Meeks, R. Nolan, B. Brackin. 1991. HLA disease association and protection in HIV infection among African Americans and Caucasians. Pathobiology 59:324.[Medline]
21. Scorza-Smeraldi, R., G. Fabio, A. Lazzarin, N. B. Elisera, M. Moroni, C. Zanussi. 1986. HLA-associated susceptibility to AIDS in Italian patients with HIV infection. Lancet 2:1187.[Medline]
22. Ivanova, R., N. Henon, V. Lepage, D. Charron, E. Vicaut, F. Schächter. 1998. HLA-DR alleles display sex-dependent effects on survival and discriminate between individual and familial longevity. Hum. Mol. Genet. 7:187.[Abstract/Free Full Text]
23. Smith, M. W., M. Dean, M. Carrington, C. Winkler, G. A. Huttley, D. A. Lomb, J. J. Goedert, T. R. O’Brien, L. P. Jacobson, R. Kaslow, et al 1997. Contrasting influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Science 277:959.[Abstract/Free Full Text]
24. Winkler, C., W. Modi, M. W. Smith, G. W. Nelson, X. Wu, M. Carrington, M. Dean, T. Honjo, K. Tashiro, D. Yabe, et al 1998. Genetic restriction of AIDS pathogenesis by an SDF1 chemokine gene variant. Science 279:389.[Abstract/Free Full Text]
25. Pantaleo, G., J. F. Demarest, T. Schacker, M. Vaccarezza, O. J. Cohen, M. Daucher, C. Graziozi, S. S. Schnittman, T. C. Quinn, G. M. Shaw, et al 1997. The qualitative nature of the primary immune response to HIV infection is a prognosticator of disease progression independent of the initial level of plasma viremia. Proc. Natl. Acad. Sci. USA 94:254.[Abstract/Free Full Text]
26. Donfield, S. M., H. S. Lynn, M. W. Hilgartner. 1998. Progression to AIDS. Science 280:1819.
27. Rowland-Jones, S., R. A. Colbert, T. Dong, S. McAdam, M. Brown, K. Ariyoshi, S. Sabally, H. Whittle, A. McMichael. 1998. Distinct recognition of closely related HIV-1 and HIV-2 cytotoxic T-cell epitopes presented by HLA-B*2703 and -B*2705. AIDS 12:1391.[Medline]
28. Johnson, R. P., A. Trocha, T. M. Buchanan, B. D. Walker. 1992. Identification of overlapping HLA class I-restricted CTL epitopes in a conserved region of the HIV-1 envelope glycoprotein: definition of minimum epitopes and analysis of the effects of sequence variations. J. Exp. Med. 175:961.[Abstract/Free Full Text]
29. Goulder, P. J. R., M. Bunce, P. Krausa, K. McIntype, S. Crowley, B. Morgan, A. Edwards, P. Giangrande, R. E. Philips, A. J. McMichael. 1996. Novel, cross-restricted, conserved, and immunodominant cytotoxic T lymphocyte epitopes in slow progressors in HIV-1 infection. AIDS Res. Hum. Retroviruses 12:1691.[Medline]
30. Klein, M. R., S. H. van der Burg, E. Hovenkamp, A. M. Holwerda, J. W. Drijhout, C. J. Melief, F. Miedema. 1998. Characterization of HLA-B57-restricted HIV-1 Gag- and RT-specific cytotoxic T lymphocyte responses. J. Gen. Virol. 79:2191.[Abstract]
31. Wilson, C. C., S. A. Kalams, B. M. Wilkes, D. J. Ruhl, F. Gao, B. H. Hahn, I. C. Hanson, K. Luzuriaga, S. Wolinsky, R. Koup, et al 1997. Overlapping epitopes in HIV-1 presented by HLA A, B, and C molecules: effects of viral variation on cytotoxic T-lymphocyte recognition. J. Virol. 71:1256.[Abstract]
32. Tomiyama, H., K. Miwa, H. Shiga, Y. I. Moore, S. Oka, A. Iwamoto, Y. Kaneko, M. Takiguchi. 1997. Evidence of presentation of multiple HIV-1 CTL epitopes by HLA-B*3501 molecules that are associated with the accelerated progression to AIDS. J. Immunol. 158:5026.[Abstract]
33. Zagury, D., A. Lachgar, V. Chams, L. S. Fall, J. Bernard, J. F. Zagury, B. Bizzini, A. Gringeri, E. Santagostino, J. Rappaport, et al 1998. IFN and Tat involvement in the immunosuppression of uninfected T cells and C-C chemokines decline in AIDS. Proc. Natl. Acad Sci. USA 95:385.
34. Gringeri, A., E. Santagostino, M. Muça-Perja, P. N. Mannucci, J. F. Zagury, B. Bizzini, A. Lachgar, M. Carcagno, J. Rappaport, M. Criscuolo, et al 1998. Safety and immunogenicity of Tat-toxoid in immunocompromised HIV-1-infected patients. J. Hum. Virol. 1:293.[Medline]

This article has been cited by other articles:

				B. J. Burwitz, C. J. Pendley, J. M. Greene, A. M. Detmer, J. J. Lhost, J. A. Karl, S. M. Piaskowski, R. A. Rudersdorf, L. T. Wallace, B. N. Bimber, et al. Mauritian Cynomolgus Macaques Share Two Exceptionally Common Major Histocompatibility Complex Class I Alleles That Restrict Simian Immunodeficiency Virus-Specific CD8+ T Cells J. Virol., June 15, 2009; 83(12): 6011 - 6019. [Abstract] [Full Text] [PDF]

				J. T. Loffredo, J. Sidney, A. T. Bean, D. R. Beal, W. Bardet, A. Wahl, O. E. Hawkins, S. Piaskowski, N. A. Wilson, W. H. Hildebrand, et al. Two MHC Class I Molecules Associated with Elite Control of Immunodeficiency Virus Replication, Mamu-B*08 and HLA-B*2705, Bind Peptides with Sequence Similarity J. Immunol., June 15, 2009; 182(12): 7763 - 7775. [Abstract] [Full Text] [PDF]

				E. Carnero, W. Li, A. V. Borderia, B. Moltedo, T. Moran, and A. Garcia-Sastre Optimization of Human Immunodeficiency Virus Gag Expression by Newcastle Disease Virus Vectors for the Induction of Potent Immune Responses J. Virol., January 15, 2009; 83(2): 584 - 597. [Abstract] [Full Text] [PDF]

				B. Emu, E. Sinclair, H. Hatano, A. Ferre, B. Shacklett, J. N. Martin, J. M. McCune, and S. G. Deeks HLA Class I-Restricted T-Cell Responses May Contribute to the Control of Human Immunodeficiency Virus Infection, but Such Responses Are Not Always Necessary for Long-Term Virus Control J. Virol., June 1, 2008; 82(11): 5398 - 5407. [Abstract] [Full Text] [PDF]

				J. T. Loffredo, A. T. Bean, D. R. Beal, E. J. Leon, G. E. May, S. M. Piaskowski, J. R. Furlott, J. Reed, S. K. Musani, E. G. Rakasz, et al. Patterns of CD8+ Immunodominance May Influence the Ability of Mamu-B*08-Positive Macaques To Naturally Control Simian Immunodeficiency Virus SIVmac239 Replication J. Virol., February 15, 2008; 82(4): 1723 - 1738. [Abstract] [Full Text] [PDF]

				C. Geldmacher, C. Gray, M. Nason, J. R. Currier, A. Haule, L. Njovu, S. Geis, O. Hoffmann, L. Maboko, A. Meyerhans, et al. A High Viral Burden Predicts the Loss of CD8 T-Cell Responses Specific for Subdominant Gag Epitopes during Chronic Human Immunodeficiency Virus Infection J. Virol., December 15, 2007; 81(24): 13809 - 13815. [Abstract] [Full Text] [PDF]

				J. T. Loffredo, J. Maxwell, Y. Qi, C. E. Glidden, G. J. Borchardt, T. Soma, A. T. Bean, D. R. Beal, N. A. Wilson, W. M. Rehrauer, et al. Mamu-B*08-Positive Macaques Control Simian Immunodeficiency Virus Replication J. Virol., August 15, 2007; 81(16): 8827 - 8832. [Abstract] [Full Text] [PDF]

				C. Geldmacher, J. R. Currier, E. Herrmann, A. Haule, E. Kuta, F. McCutchan, L. Njovu, S. Geis, O. Hoffmann, L. Maboko, et al. CD8 T-Cell Recognition of Multiple Epitopes within Specific Gag Regions Is Associated with Maintenance of a Low Steady-State Viremia in Human Immunodeficiency Virus Type 1-Seropositive Patients J. Virol., March 1, 2007; 81(5): 2440 - 2448. [Abstract] [Full Text] [PDF]

				H. Horton, I. Frank, R. Baydo, E. Jalbert, J. Penn, S. Wilson, J. P. McNevin, M. D. McSweyn, D. Lee, Y. Huang, et al. Preservation of T Cell Proliferation Restricted by Protective HLA Alleles Is Critical for Immune Control of HIV-1 Infection J. Immunol., November 15, 2006; 177(10): 7406 - 7415. [Abstract] [Full Text] [PDF]

				H. Horton, C. Havenar-Daughton, D. Lee, E. Moore, J. Cao, J. McNevin, T. Andrus, H. Zhu, A. Rubin, T. Zhu, et al. Induction of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Responses in HIV Vaccine Trial Participants Who Subsequently Acquire HIV-1 Infection J. Virol., October 1, 2006; 80(19): 9779 - 9788. [Abstract] [Full Text] [PDF]

				J. L. Heeney, A. G. Dalgleish, and R. A. Weiss Origins of HIV and the evolution of resistance to AIDS. Science, July 28, 2006; 313(5786): 462 - 466. [Abstract] [Full Text] [PDF]

				E. L. Turnbull, A. R. Lopes, N. A. Jones, D. Cornforth, P. Newton, D. Aldam, P. Pellegrino, J. Turner, I. Williams, C. M. Wilson, et al. HIV-1 Epitope-Specific CD8+ T Cell Responses Strongly Associated with Delayed Disease Progression Cross-Recognize Epitope Variants Efficiently J. Immunol., May 15, 2006; 176(10): 6130 - 6146. [Abstract] [Full Text] [PDF]

				E. C. Speelmon, D. Livingston-Rosanoff, S. S. Li, Q. Vu, J. Bui, D. E. Geraghty, L. P. Zhao, and M. J. McElrath Genetic Association of the Antiviral Restriction Factor TRIM5{alpha} with Human Immunodeficiency Virus Type 1 Infection J. Virol., March 1, 2006; 80(5): 2463 - 2471. [Abstract] [Full Text] [PDF]

				D. G. Kavanagh, D. E. Kaufmann, S. Sunderji, N. Frahm, S. Le Gall, D. Boczkowski, E. S. Rosenberg, D. R. Stone, M. N. Johnston, B. S. Wagner, et al. Expansion of HIV-specific CD4+ and CD8+ T cells by dendritic cells transfected with mRNA encoding cytoplasm- or lysosome-targeted Nef Blood, March 1, 2006; 107(5): 1963 - 1969. [Abstract] [Full Text] [PDF]

				A. Rios, J. M. Rodriguez, M. R. Moya, P. J. Galindo, M. Canteras, M. R. Alvarez, and P. Parrilla Associations of HLA-C Alleles With Multinodular Goiters: Study in a Population From Southeastern Spain. Arch Surg, February 1, 2006; 141(2): 123 - 128. [Abstract] [Full Text] [PDF]

				J. T. Loffredo, J. Sidney, S. Piaskowski, A. Szymanski, J. Furlott, R. Rudersdorf, J. Reed, B. Peters, H. D. Hickman-Miller, W. Bardet, et al. The High Frequency Indian Rhesus Macaque MHC Class I Molecule, Mamu-B*01, Does Not Appear to Be Involved in CD8+ T Lymphocyte Responses to SIVmac239 J. Immunol., November 1, 2005; 175(9): 5986 - 5997. [Abstract] [Full Text] [PDF]

				A. Milicic, D. A. Price, P. Zimbwa, B. L. Booth, H. L. Brown, P. J. Easterbrook, K. Olsen, N. Robinson, U. Gileadi, A. K. Sewell, et al. CD8+ T Cell Epitope-Flanking Mutations Disrupt Proteasomal Processing of HIV-1 Nef J. Immunol., October 1, 2005; 175(7): 4618 - 4626. [Abstract] [Full Text] [PDF]

				T. Ndung'u, S. Gaseitsiwe, E. Sepako, F. Doualla-Bell, T. Peter, S. Kim, I. Thior, V. A. Novitsky, and M. Essex Major Histocompatibility Complex Class II (HLA-DRB and -DQB) Allele Frequencies in Botswana: Association with Human Immunodeficiency Virus Type 1 Infection Clin. Vaccine Immunol., September 1, 2005; 12(9): 1020 - 1028. [Abstract] [Full Text] [PDF]

				F. Bernardin, D. Kong, L. Peddada, L. A. Baxter-Lowe, and E. Delwart Human Immunodeficiency Virus Mutations during the First Month of Infection Are Preferentially Found in Known Cytotoxic T-Lymphocyte Epitopes J. Virol., September 1, 2005; 79(17): 11523 - 11528. [Abstract] [Full Text] [PDF]

				H. Sung, S.-M. Kang, M.-S. Lee, T. G. Kim, and Y.-K. Cho Korean Red Ginseng Slows Depletion of CD4 T Cells in Human Immunodeficiency Virus Type 1-Infected Patients Clin. Vaccine Immunol., April 1, 2005; 12(4): 497 - 501. [Abstract] [Full Text] [PDF]

				J. T. Loffredo, J. Sidney, C. Wojewoda, E. Dodds, M. R. Reynolds, G. Napoe, B. R. Mothe, D. H. O'Connor, N. A. Wilson, D. I. Watkins, et al. Identification of Seventeen New Simian Immunodeficiency Virus-Derived CD8+ T Cell Epitopes Restricted by the High Frequency Molecule, Mamu-A*02, and Potential Escape from CTL Recognition J. Immunol., October 15, 2004; 173(8): 5064 - 5076. [Abstract] [Full Text] [PDF]

				D. H. O'Connor, B. R. Mothe, J. T. Weinfurter, S. Fuenger, W. M. Rehrauer, P. Jing, R. R. Rudersdorf, M. E. Liebl, K. Krebs, J. Vasquez, et al. Major Histocompatibility Complex Class I Alleles Associated with Slow Simian Immunodeficiency Virus Disease Progression Bind Epitopes Recognized by Dominant Acute-Phase Cytotoxic-T-Lymphocyte Responses J. Virol., August 15, 2003; 77(16): 9029 - 9040. [Abstract] [Full Text] [PDF]

				B. A. P. Lafont, A. Buckler-White, R. Plishka, C. Buckler, and M. A. Martin Characterization of Pig-Tailed Macaque Classical MHC Class I Genes: Implications for MHC Evolution and Antigen Presentation in Macaques J. Immunol., July 15, 2003; 171(2): 875 - 885. [Abstract] [Full Text] [PDF]

				H. Dehghani, B. A. Puffer, R. W. Doms, and V. M. Hirsch Unique Pattern of Convergent Envelope Evolution in Simian Immunodeficiency Virus-Infected Rapid Progressor Macaques: Association with CD4-Independent Usage of CCR5 J. Virol., June 1, 2003; 77(11): 6405 - 6418. [Abstract] [Full Text] [PDF]

				P. O. Flores-Villanueva, H. Hendel, S. Caillat-Zucman, J. Rappaport, A. Burgos-Tiburcio, S. Bertin-Maghit, J. A. Ruiz-Morales, M. E. Teran, J. Rodriguez-Tafur, and J.-F. Zagury Associations of MHC Ancestral Haplotypes with Resistance/Susceptibility to AIDS Disease Development J. Immunol., February 15, 2003; 170(4): 1925 - 1929. [Abstract] [Full Text] [PDF]

				V. Novitsky, P. Gilbert, T. Peter, M. F. McLane, S. Gaolekwe, N. Rybak, I. Thior, T. Ndung'u, R. Marlink, T. H. Lee, et al. Association between Virus-Specific T-Cell Responses and Plasma Viral Load in Human Immunodeficiency Virus Type 1 Subtype C Infection J. Virol., December 20, 2002; 77(2): 882 - 890. [Abstract] [Full Text] [PDF]

				T. Muhl, M. Krawczak, P. ten Haaft, G. Hunsmann, and U. Sauermann MHC Class I Alleles Influence Set-Point Viral Load and Survival Time in Simian Immunodeficiency Virus-Infected Rhesus Monkeys J. Immunol., September 15, 2002; 169(6): 3438 - 3446. [Abstract] [Full Text] [PDF]

				J. Tang, S. Tang, E. Lobashevsky, A. D. Myracle, U. Fideli, G. Aldrovandi, S. Allen, R. Musonda, and R. A. Kaslow Favorable and Unfavorable HLA Class I Alleles and Haplotypes in Zambians Predominantly Infected with Clade C Human Immunodeficiency Virus Type 1 J. Virol., July 19, 2002; 76(16): 8276 - 8284. [Abstract] [Full Text] [PDF]

				J. Tang, B. Shelton, N. J. Makhatadze, Y. Zhang, M. Schaen, L. G. Louie, J. J. Goedert, E. C. Seaberg, J. B. Margolick, J. Mellors, et al. Distribution of Chemokine Receptor CCR2 and CCR5 Genotypes and Their Relative Contribution to Human Immunodeficiency Virus Type 1 (HIV-1) Seroconversion, Early HIV-1 RNA Concentration in Plasma, and Later Disease Progression J. Virol., January 15, 2002; 76(2): 662 - 672. [Abstract] [Full Text] [PDF]

				V. Novitsky, N. Rybak, M. F. McLane, P. Gilbert, P. Chigwedere, I. Klein, S. Gaolekwe, S. Y. Chang, T. Peter, I. Thior, et al. Identification of Human Immunodeficiency Virus Type 1 Subtype C Gag-, Tat-, Rev-, and Nef-Specific Elispot-Based Cytotoxic T-Lymphocyte Responses for AIDS Vaccine Design J. Virol., October 1, 2001; 75(19): 9210 - 9228. [Abstract] [Full Text] [PDF]

				R. A. Kaslow, C. Rivers, J. Tang, T. J. Bender, P. A. Goepfert, R. El Habib, K. Weinhold, M. J. Mulligan, and the NIAID Aids Vaccine Evaluation Group Polymorphisms in HLA Class I Genes Associated with both Favorable Prognosis of Human Immunodeficiency Virus (HIV) Type 1 Infection and Positive Cytotoxic T-Lymphocyte Responses to ALVAC-HIV Recombinant Canarypox Vaccines J. Virol., September 15, 2001; 75(18): 8681 - 8689. [Abstract] [Full Text] [PDF]

				T. M. Williams Human Leukocyte Antigen Gene Polymorphism and the Histocompatibility Laboratory J. Mol. Diagn., August 1, 2001; 3(3): 98 - 104. [Abstract] [Full Text] [PDF]

				L. F. Ross Genetic Exceptionalism vs. Paradigm Shift: Lessons from HIV J. Law Med. Ethics, June 1, 2001; 29(2): 141 - 148. [PDF]

				C. M. Hogan and S. M. Hammer Host Determinants in HIV Infection and Disease: Part 2: Genetic Factors and Implications for Antiretroviral Therapeutics Ann Intern Med, May 15, 2001; 134(10): 978 - 996. [Abstract] [Full Text] [PDF]

				L. F. Ross Genetic Exceptionalism vs. Paradigm Shift: Lessons from HIV J. Law Med. Ethics, March 1, 2001; 29(1): 141 - 148. [PDF]

				S. Goldstein, C. R. Brown, H. Dehghani, J. D. Lifson, and V. M. Hirsch Intrinsic Susceptibility of Rhesus Macaque Peripheral CD4+ T Cells to Simian Immunodeficiency Virus In Vitro Is Predictive of In Vivo Viral Replication J. Virol., October 15, 2000; 74(20): 9388 - 9395. [Abstract] [Full Text]

				S. A. Migueles, M. S. Sabbaghian, W. L. Shupert, M. P. Bettinotti, F. M. Marincola, L. Martino, C. W. Hallahan, S. M. Selig, D. Schwartz, J. Sullivan, et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors PNAS, March 14, 2000; 97(6): 2709 - 2714. [Abstract] [Full Text] [PDF]

				P. O. Flores-Villanueva, E. J. Yunis, J. C. Delgado, E. Vittinghoff, S. Buchbinder, J. Y. Leung, A. M. Uglialoro, O. P. Clavijo, E. S. Rosenberg, S. A. Kalams, et al. Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity PNAS, April 24, 2001; 98(9): 5140 - 5145. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hendel, H. Articles by Zagury, J.-F. Search for Related Content PubMed PubMed Citation Articles by Hendel, H. Articles by Zagury, J.-F.