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The Journal of Immunology, 2007, 179, 7916 -7923
Copyright © 2007 by The American Association of Immunologists, Inc.
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Fc{gamma}RIIa Genotype Predicts Progression of HIV Infection1

Donald N. Forthal2,*, Gary Landucci*, Jay Bream{dagger}, Lisa P. Jacobson{ddagger}, Tran B. Phan* and Benjamin Montoya*

* Division of Infectious Diseases, Department of Medicine, University of California, Irvine School of Medicine, Irvine, CA 92697; and {dagger} Disease Prevention and Control Program, Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, and {ddagger} Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Polymorphisms in Fc{gamma}R genes are associated with susceptibility to or severity of a number of autoimmune and infectious diseases. We found that HIV-infected men in the Multicenter AIDS Cohort Study with the Fc{gamma}RIIa RR genotype progressed to a CD4+ cell count of <200/mm3 at a faster rate than individuals with the RH or HH genotypes (relative hazard = 1.6; p = 0.0001). However, progression to AIDS (using the broad definition of either a CD4+ cell count <200/mm3 or development of an AIDS-defining illness) was less impacted by Fc{gamma}RIIa genotype, largely because HH homozygotes had an increased risk of Pneumocystis jiroveci pneumonia as an AIDS-defining illness. We also showed that chronically infected subjects develop a substantial anti-gp120-specific IgG2 response. Moreover, HIV-1 immune complexes are more efficiently internalized by monocytes from HH subjects compared with RR subjects, likely because of the presence of IgG2 in the complexes. Finally, the Fc{gamma}RIIIa F/V gene polymorphism was not associated with progression of HIV infection, but, as demonstrated previously, did predict the risk of Kaposi’s sarcoma. These results demonstrate the importance of Fc{gamma}Rs in AIDS pathogenesis and point toward a critical role for interactions between Fc{gamma}Rs and immune complexes in disease progression.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Human immunodeficiency virus (HIV) infection is characterized by a potent, yet inefficient, HIV-specific Ab response. As a result of the high level of Abs, a large proportion of circulating virus exists as immune complexes during the chronic, viremic phase of infection (1, 2). Immune complexes may also form from nonviral components during HIV infection (3, 4, 5). For example, patients with chronic infection have both circulating LPS and anti-LPS Abs; bacterial components such as LPS have been implicated as a cause of immune activation during HIV infection (5).

The biological effect of immune complexes often depends on their engagement of receptors for the Fc segment of IgG (Fc{gamma}Rs) on the surface of cells such as monocytes, macrophages, and dendritic cells (6). These cells play important roles in HIV infection because they are susceptible to infection and they are potentially components of anti-HIV immunity or pathogenesis (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17). The Fc{gamma}Rs found on these cells include Fc{gamma}RI (CD64), Fc{gamma}RIIa and IIb (CD32), and Fc{gamma}RIIIa (CD16) (18). Both Fc{gamma}RIIa and Fc{gamma}RIIIa are encoded by genes having functional polymorphisms that affect IgG binding affinity (19, 20, 21). In the case of Fc{gamma}RIIa, the gene encodes either a histidine (H) or arginine (R) at amino acid position 131 (19, 20). At least one H is required for binding to IgG2, and HH and RH receptors also bind IgG3 with higher affinity than RR receptors (21, 22). Outside of Asia, the HH and RR genotypes each occur in ~25% of the population, and the RH genotype occurs in ~50% (23, 24). There is marked skewing of this distribution in East Asia, where 50–60% of individuals are H homozygotes and <10% carry the RR genotype (23, 25, 26).

Fc{gamma}RIIIa is encoded by a gene that confers either a valine (V) or phenylalanine (F) at amino acid 158 (27). Genotype frequencies are fairly similar throughout the world with VV found in ~10–20% and FV and FF each occurring in ~45% of the population (23, 26, 28). IgG1 and IgG3 bind with higher affinity to the V form of the receptor than to the F form (22, 29). Both Fc{gamma}RIIa and IIIa genotypes have been associated with susceptibility to or severity of a number of autoimmune and infectious diseases (30, 31, 32, 33, 34, 35, 36).

Because Fc{gamma}R polymorphisms affect the binding and clearance of immune complexes and because immune complexes are a common feature of HIV infection known to have a number of immunomodulating effects and pathological consequences, we determined whether Fc{gamma}RIIa or Fc{gamma}RIIIa genotypes were associated with progression of HIV infection.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Disclosures
 References
 
Study subjects

Genotyping results from a total of 559 infected participants in the Multicenter AIDS Cohort Study (MACS)3 were analyzed. Subjects were enrolled in MACS between 1984 and 2006. More than 50% of the subjects were diagnosed with HIV infection by 1985, 75% by 1988, and 90% by 1992; all but 23 subjects were diagnosed with HIV infection before 1996 (when highly active antiretroviral therapy became available). Five hundred and fifty-eight subjects were successfully genotyped at the Fc{gamma}RIIa gene locus and 557 at the Fc{gamma}RIIIa locus. Subjects included 432 with known seroconversion dates within 2 years (166 ≤ 0.5 year, 214 0.55–0.75 year, 17 0.755–1.0 year, 23 1.05–1.5 years, and 12 1.55–2.00 years). The remaining 127 subjects entered the study seropositive in 1984 with CD4+ cell counts >500. All subjects were male, and 482 (86%) were identified as white/nonHispanic, 25 (4%) as white/Hispanic, 47 (8%) as black/nonHispanic, 1 as black/Hispanic, and 4 as Asian/Pacific Islander or other. Median age at the time of HIV positivity (or enrollment in MACS) was 34 years (range 20–62 years). This research has been reviewed by the UC Irvine Institutional Review Board.

Fc{gamma}RIIa and IIIa genotyping

DNA was extracted from PBMCs or transformed B lymphocytes using Qiagen DNeasy tissue kits or Corbett Xtractor according to the manufacturer’s instructions. Genotyping was performed using methods based on those of Dall’Ozzo, et al. (37). Sample DNA was used to amplify the region of the Fc{gamma}RIIa gene spanning the single nucleotide polymorphism at position 494. A common forward primer (5'-CAATTTTGCTGCTATGGGC-3') was used in combination with the H (5'-GCGGGCATCCCAGAAATTCTCCCA-3') or R allele primer (5'-GCGGGCAGGGCGGCATCCCAGAAATTCTCCCG-3') in separate 25 µl reactions. The H allele primer included a 6-base GC tail and the R allele primer included a 14-base GC tail. DNA and primers were added to Eurogentec qPCR Mastermix Plus for SYBR Green I–No ROX, and amplification was performed with a Rotor-Gene 3000 thermocycler using the following parameters: 95°C for 10 min, followed by 40 cycles at 95°C (60 s), 57.5°C (30 s), and 72°C (60 s). Once amplification was complete, melt curves were obtained from +0.5°C stepwise increments (72–95°C) of 10 s each. Positive controls for all genotypes were included in each assay; the genotypes of control samples were verified by sequencing the Fc{gamma}RIIa gene in the region of the polymorphism. For some samples with DNA of poor quality or low quantity, a first-step PCR was used to enrich for Fc{gamma}RIIa product, followed by the procedure described above.

Fc{gamma}RIIIa genotypes were determined using a similar strategy, except that the primers were designed to allow melt curve differentiation of the alleles in a single PCR. A common forward primer (5'-TCCAAAAGCCACACTCAAAGTC-3') was used with either V-specific (5'-GCGGGCAGGGCGGCAGACACATTTTTACTCCCATC-3') or F-specific (5'-GCGGGCTCACACATTTTTACTCCCATA-3') reverse primers. The following thermocycler parameters were used: 95°C for 10 min, followed by 50 cycles at 95°C (20 s), 57°C (60 s), and 72°C (45 s). As in the case of Fc{gamma}RIIa, a primary enrichment step was also used for some samples.

Internalization of HIV-1 immune complexes

HIV-1 was labeled with FITC using a modification of methods described by Hartshorn, et al. (38). In brief, FITC stock was prepared at 1.0 mg/ml in sodium carbonate buffer. Virus stock was mixed with FITC stock (10:1 by volume) for 1 h and dialyzed against PBS for 18 h in 300 kd dialysis membranes. The pore size is adequate to exclude FITC, monomeric, and dimeric soluble gp120 from FITC-labeled virions. Immune complexes were produced by incubating 50 µl of 0.05 mg/ml polyclonal HIV-positive IgG with 105 tissue culture-infective dose (TCID50) of the FITC-labeled HIV-1 for 30 min at 37°C. Based on neutralization assays, these concentrations of virus and Ab likely result in Ab excess. In some experiments, IgG2 was depleted from IgG by use of an ImmunoPure streptavidin column (Pierce) bound with biotin-conjugated mouse anti-human IgG2. HIV-positive IgG from pooled serum was passed through the column and the unbound fraction collected. The IgG2-depleted sample was assayed for Ig subclasses by the University of California Irvine Medical Center clinical laboratory using nephelometry. After depletion, IgG2 was below the range of detection (<10 mg/L).

To quantify internalization of HIV immune complexes, fresh PBMCs from Fc{gamma}RIIa-genotyped healthy donors (enrolled in the Normal Blood Donors Program at the University of California, Irvine) were incubated with either medium, with FITC-labeled HIV-1 and HIV-negative control IgG, or with immune complexes (FITC-labeled HIV-1 and HIV-positive polyclonal or IgG2-depleted IgG) for 30 min at 37°C on a shaker platform. Cells were then washed, treated with trypsin to remove bound but unphagocytosed complexes, re-washed, and stained with PC5-labeled anti-CD14 Ab (Beckman Coulter), and fixed with 2% paraformaldehyde. The percentage of CD14+ cells staining with FITC was determined using a FACSCalibur (BD Biosciences) and analyzed with CellQuest software (BD Biosciences). Background FITC staining of cells due to labeled virus in the absence of specific Ab was subtracted from immune complex staining.

Quantification of serum anti-gp120 IgG1 and IgG2

Titers of IgG1 and IgG2 subclass specific Ab to gp120 were determined by ELISA. Flat bottom 96-well microtiter plates (Costar) were coated with 100 µl of 1 µg/ml HIV-1MN rgp120 (Vaxgen) overnight at room temperature. Plates were then washed and blocked with 200 µl of buffer consisting of 1% BSA, 5% sucrose, and 0.05% NaN3 in PBS. 100 µl of serial dilutions of heat-inactivated plasma or IgG were added to duplicate wells and incubated for 2 h at 37°C. After washing, 100 µl of biotin-conjugated mAb against human IgG1 (1:500) or IgG2 (1:1000) (Sigma-Aldrich) was added to wells and incubated for an additional 1 h at 37°C. Plates were washed further and 100 µl of HRP-streptavidin (1:6000; Southern Biotechnology Associates) was added for 30 min at 37°C. After additional washes, 100 µl of tetramethylbenzidine substrate (Sigma-Aldrich) was added. Color was stopped, and OD was determined in an ELISA plate reader. Positive and negative pooled plasma samples were used as controls. Samples with OD’s greater than 0.1 OD were considered positive; mean OD plus 3 SDs for negative control replicates was always below 0.1.

Statistical analyses

To determine whether genotype predicted disease progression among infected subjects, we used Cox proportional hazard models; race and age at the time of seroconversion (or entry in MACS) were included as covariates in the model. {chi}2 tests or logistical regression analyses were used to explore relationships between genotype and AIDS-defining diagnoses, and Kruskal-Wallis statistics were used to evaluate the impact of genotype on viral load set point.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Disclosures
 References
 
Fc{gamma}RIIa genotype and disease progression

Using subjects who either seroconverted or entered the MACS cohort seropositive with CD4+ cell counts >500/mm3, we determined whether Fc{gamma}RIIa genotype was associated with clinical or laboratory markers of disease progression. In a Cox proportional hazard model including age and race, Fc{gamma}RIIa genotype predicted the rate of progressing to a CD4+ cell count <200/mm3 (p = 0.001; Fig. 1A). Homozygous RR subjects had a relative hazard of 1.6 (95% confidence interval (CI) = 1.2–2.3; p = 0.0001) compared with subjects with any H allele. Similar results were obtained when only those subjects who seroconverted after enrollment in MACS were analyzed (n = 425; relative hazard = 1.6, 95% CI = 1.2–2.1; p = 0.003 for RRs vs any H allele). The genotype distribution among seroconverters was similar to the distribution among subjects who were seropositive at enrollment (p = 0.4). Using only subjects who were infected in 1990 or earlier (n = 468), we again found an overall relationship between Fc{gamma}RIIa genotype (p = 0.01), and the RR subjects again had a faster rate of progression than the other genotypes (relative hazard = 1.5; p = 0.003). Thus, it is unlikely that treatment with highly active antiretroviral therapy (which was not widely available before 1996) impacted the relationship between genotype and disease progression.


Figure 1
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  		FIGURE 1. Fc{gamma}RIIa genotype is associated with progression to a CD4+ cell count <200/mm3 (A; n = 550, p = 0.001). A similar effect of Fc{gamma}RIIa genotype on progression to AIDS, defined as a having a CD4+ cell count <200/mm3 or an AIDS-defining illness, was found, but the effect was of less magnitude and overall was not statistically significant (n = 556, p = 0.08; B). The x-axis label "Years" refers to years after seroconversion for subjects with known seroconversion dates (n = 425 in A and 430 in B) and years after enrolling in MACS for subjects whose seroconversion dates were not known (n = 125 in A and 126 in B).

 
Overall, there was a trend toward Fc{gamma}RIIa genotype predicting progression to AIDS, defined as a CD4+ cell count <200 or an AIDS-defining illness (p = 0.08; Fig. 1B), and subjects with the RR genotype had a higher rate of progression than those with any H allele (relative hazard = 1.3, 95% CI = 1.0–1.6; p = 0.05). The reason for the dampened effect of Fc{gamma}RIIa genotype on progression to AIDS is that the genotype, while having a significant effect on reaching a CD4+ cell count <200/mm3, had no overall effect on developing an AIDS-defining illness (p = 0.3). These seemingly contradictory results suggested that the RR genotype might be associated with a lower risk of certain AIDS-defining illnesses. Indeed, there was an overall association between Fc{gamma}RIIa genotype and AIDS-defining diagnosis (p = 0.03, {chi}2). In particular, RR subjects were ~2.5 times less likely to acquire Pneumocystis jiroveci (carinii) pneumonia as their AIDS-defining illness than subjects with the HH genotype (odds ratio (OR) = 0.4; 95% CI = 0.2–0.8; p = 0.008, logistic regression; Table I). In a Cox proportional hazard model including race and age, Fc{gamma}RIIa genotype was a significant predictor of progression to AIDS (p = 0.009) when restricting the analysis to subjects whose AIDS-defining illness was not Pneumocystis carinii pneumonia.


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  		Table I. Risk of P. jiroveci pneumonia as an AIDS-defining illness

 
Although the HH genotype was associated with an increased risk of P. jiroveci pneumonia as an AIDS-defining diagnosis, this relationship did not hold up when considering primary cases of PCP that occurred at any time (p = 0.5). In fact, the RR genotype was associated with a 2.3-fold higher risk of P. jiroveci pneumonia infection among subjects who developed P. jiroveci pneumonia subsequent to their AIDS defining illness (p = 0.009), most likely because of the effect of Fc{gamma}RIIa genotype on the rate of developing a CD4+ cell count <200/mm3. When considering only subjects whose CD4+ cell count dropped to <200/mm3 or who developed P. jiroveci pneumonia, homozygous HH subjects did have a higher risk of P. jiroveci pneumonia than RR subjects (OR = 1.6; p = 0.1) or RH subjects (OR = 1.8; p = 0.06); when HH subjects were compared with those with any R allele, this relationship became statistically significant (OR = 1.7; p = 0.05). Furthermore, among those who developed P. jiroveci pneumonia and for whom CD4+ cell counts were available at the time of the episode (n = 95), those with the HH genotype were more likely to have a CD4+ cell count ≥100/mm3 than were RR subjects (n = 59; OR = 2.9; p = 0.05). Thus, it would appear that HH subjects are at increased risk of P. jiroveci pneumonia, particularly among those with relatively higher (≥100/mm3) CD4+ cell counts. However, CD4+ cell count exerts a greater effect than genotype.

Fc{gamma}RIIa genotype was not associated with viral load set point, defined as plasma HIV RNA level at ~18 mo after the first seropositive visit (p = 0.8; Fig. 2). When viral load was entered into the Cox proportional hazard model as either a continuous variable or as a categorical variable (bifurcated at the median value), the relationship between Fc{gamma}RIIa genotype and progression to a CD4+ cell count <200/mm3 remained significant (data not shown). In fact, the RR genotype was a slightly stronger predictor of progression to a CD4+ cell count <200/mm3 (relative hazard = 1.5, 95% CI = 1.1–2.1; p = 0.007) than was a viral load greater than the median (relative hazard = 1.4, 95% CI = 1.1–1.9; p = 0.02) when both terms were included in the model.


Figure 2
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  		FIGURE 2. Fc{gamma}RIIa genotype is not associated with viral load set point (p = 0.8). Viral load set point was defined as HIV RNA copies/ml at ~18 mo after seroconversion or after enrollment in MACS (for subjects who were seropositive on entry).

 
In summary, the Fc{gamma}RIIa RR genotype is associated with an increased rate of progressing to a CD4+ cell count <200/mm3 and impacts CD4+ cell count independently of viral load. Moreover, the HH genotype appears to increase the risk of developing P. jiroveci pneumonia as an AIDS-defining illness.

Fc{gamma}RIIa genotype is associated with the degree of in vitro internalization of HIV-1 immune complexes (ICs)

The Fc{gamma}RIIa alleles result in receptors that are phenotypically different with respect to binding of ICs, particularly those consisting of IgG2 (21). The RR receptor binds with the lowest avidity to such complexes and the HH receptor binds with the highest avidity. Phagocytosis of Ab-coated bacterial and other particles is less efficient in RR receptors than in HH receptors (39, 40). We investigated whether monocyte internalization of HIV-1 coated with polyclonal IgG from HIV-infected subjects also differed by genotype. To measure internalization, HIV-ICs were incubated with PBMCs for 30 min at 37°C. Unbound and bound, but noninternalized, complexes were removed by washing and trypsinization, and CD14+ cells containing FITC-labeled HIV-1 were analyzed by cytometry as described above. The percentage of monocytes containing internalized HIV-1 ICs, after adjustment for internalization of uncomplexed HIV-1, was higher for Fc{gamma}RIIa HH donors than for either RH or RR donors (median = 18.0%, 11.4%, and 5.3% for HH, RH, and RR donors, respectively; p = 0.01 by ANOVA on logit-transformed data; Fig. 3A). With post hoc adjustments, differences were statistically significant when HH donors were compared with RR donors (p = 0.008), but the difference between HH and RH or RH and RR donors was not (p = 0.5 and 0.2, respectively). There were no genotype differences in the internalization of uncomplexed HIV-1 (p = 0.9; Fig. 3B).


Figure 3
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  		FIGURE 3. Monocyte internalization of HIV-immune complexes is dependent on Fc{gamma}RIIa genotype (A). Monocytes phagocytosing HIV-1 immune complexes were identified by dual CD14-PE/HIV-1-FITC staining; the percentage of monocytes phagocytosing uncomplexed HIV-1 (B) was subtracted from the percentage phagocytosing HIV-1 immune complexes to obtain the data represented in A. By ANOVA, there are statistically significant differences between the genotypes with respect to internalizing HIV-1 immune complexes (p = 0.01); with post hoc adjustments, differences were statistically significant when HH donors were compared with RR donors (p = 0.008), but the difference between HH and RH or RH and RR donors was not (p = 0.5 and 0.2, respectively). There were no genotype differences in the internalization of uncomplexed HIV (p = 0.9). Depletion of IgG2 from HIV-seropositive IgG leads to a decrease in internalization by monocytes from HH donors, but has little or no impact on internalization by monocytes from RR donors (C).

 
The increased internalization by monocytes from HH donors suggested that IgG2 was an important contributor to the makeup of HIV-1-specific Ab. To test this likelihood, HIV-positive polyclonal IgG was depleted of IgG2 before incubating with FITC-labeled HIV-1. The depletion of IgG2 led to reduced internalization in HH donors but had no effect on internalization by monocytes from RR donors (Fig. 3C).

We also directly quantified anti-gp120 IgG2 levels in the pooled IgG used to make immune complexes and in nine individual sera from chonically infected subjects. The pooled IgG had a gp120-specific IgG2 titer of 1:8000, compared with a gp120-specific IgG1 titer of 1:90, 510. All of the individual sera tested also had detectable anti-gp120 IgG2 (geometrical mean titer = 1:6442, range = 1:2828 – 1:22, 627), and the ratios of IgG2:IgG1 ranged from 0.03 to 0.25 (mean = 0.16).

Our results indicate that, as with ICs made from other Ags and Abs, the Fc{gamma}RIIa genotype impacts the degree of internalization. By extending this finding to the particular case of HIV-1 ICs and by demonstrating the presence of an anti-Env IgG2 response, we have underlined the potential role of anti-HIV-1 IgG2 in modifying important Fc{gamma}R-triggered biological phenomena such as phagocytosis and endocytosis.

Fc{gamma}RIIIa genotype and disease progression

Unlike Fc{gamma}RIIa, there was no association between Fc{gamma}RIIIa genotype and disease progression, measured as either achieving a CD4+ cell count <200/mm3 (p = 0.3; Fig. 4A) or progressing to AIDS (p = 0.4; Fig. 4B).


Figure 4
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  		FIGURE 4. Fc{gamma}RIIIa genotype does not predict progression to a CD4+ cell count <200/mm3 (n = 549, p = 0.3; A) or to AIDS (n = 555, p = 0.4; B).

 
Fc{gamma}RIIIa genotype was, however, associated with the risk of developing Kaposi’s sarcoma (KS; p = 0.003; logistic regression). Subjects with the VV genotype were more likely to have KS than were subjects with the FF genotype (OR = 3.0; p = 0.002), whereas those with the FV genotype had an intermediate risk (OR = 1.6; p = 0.1 compared with FFs; Table II). There was a trend toward an association between Fc{gamma}RIIa genotype and the risk of KS (p = 0.09). However, this trend likely resulted from the reported Fc{gamma}RIIa-Fc{gamma}RIIIa linkage disequilibrium (23), because logistic regression analysis including both Fc{gamma}RIIa and IIIa genotypes in the model demonstrated a strong association between KS and Fc{gamma}RIIIa (p = 0.006) but none between KS and Fc{gamma}RIIa (p = 0.7). Our results are similar to those of Lehrnbecher et al., who first reported a lower risk of KS (and of human herpes virus type 8 infection) in HIV-infected subjects with the FF genotype compared with the FV genotype (36). However, unlike their results, we found a higher risk among VVs and, therefore, a dose response with FF, FV, and VV genotypes conferring respectively greater risk.


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  		Table II. Risk of Kaposi’s sarcoma by Fc{gamma}RIIIa genotype

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Disclosures
 References
 
We have explored the relationship between two polymorphic Fc{gamma}R genes and the rate of clinical and immunological progression of HIV infection. Our results indicate that the Fc{gamma}RIIa genotype influences the rate of CD4+ cell decline and the risk of acquiring P. jiroveci pneumonia as an AIDS-defining illness. Fc{gamma}RIIIa genotype, in contrast, does not appear to be a major determinant of immunological progression but, as reported by others, influences the risk of developing KS (36).

Fc{gamma}RIIa genotype has been associated with several autoimmune and infectious diseases. For example, individuals with the RR genotype have about a 1.5-fold increased risk of systemic lupus erythematosus than do individuals with the HH genotype (30). Some studies, but not others, have found an increased risk of invasive pneumococcal or meningococcal disease with the RR genotype (31, 32, 41, 42). In contrast, RR patients may be protected from severe malaria (33). Thus, in diseases associated with pathogenic or infectious immune complexes, the less efficiently phagocytic RR genotype is disadvantageous. The high affinity HH genotype may be disadvantageous where immune-complexed pathogens establish infection within phagocytes or where IgG2 Abs block beneficial Fc{gamma}R-triggered events. With respect to HIV, Brouwer et al. reported a 2-fold increased risk of perinatal infection in HH infants compared with RR infants (35). They suggested that maternal Ab bound to virus may have facilitated infection of macrophages or dendritic cells bearing the higher affinity HH receptor.

We have shown, for the first time, that Fc{gamma}RIIa genotype is associated with the rate at which HIV infection progresses. This relationship is strongest when progression is defined as reaching a CD4+ cell count <200/mm3 and subjects with the low affinity RR receptor progress with the highest rate. Viral load has little, if any, impact on the relationship between Fc{gamma}RIIa genotype and the rate at which a CD4+ cell count <200/mm3 is achieved. We have no direct evidence in support of a particular mechanism by which the Fc{gamma}RIIa gene polymorphism might impact the progression of HIV infection in this manner. However, the R receptor has been previously shown to have weaker binding to ICs made of IgG2 or IgG3 than the H receptor (21). We have shown that HIV-1 immune complexes are also internalized less efficiently in vitro by monocytes bearing the RR receptor than by those bearing the HH receptor. ICs have a number of pathological consequences and have been shown to promote T cell activation, which is strongly correlated with progression of infection (43, 44, 45, 46, 47). The efficiency of IC internalization may therefore be playing a role in immune activation, CD4+ cell loss, and disease progression. Although HIV-1 ICs are clearly present, other ICs are also likely to be found during the course of HIV infection. The demonstration of both elevated plasma LPS levels and anti-LPS Abs during chronic infection indicate the likely presence of circulating ICs made of bacterial components, possibly translocated from the gut (5). Interestingly, IgG2 is a major Ab subclass directed against bacterial components (48, 49, 50). Others have previously shown, as have we in this study, that internalization of ICs made with IgG2 are the most impacted by the Fc{gamma}RIIa polymorphism (20, 21, 22). Furthermore, we have demonstrated that anti-Env IgG2 responses may be common during chronic HIV infection. It is possible that less efficient binding and internalization of ICs, particularly bacterial or viral ICs consisting of IgG2, results in an equilibrium favoring the triggering of toll-like or other pattern recognition receptors leading to T cell activation and subsequent loss of CD4+ cells. Arguing against this possibility is the demonstration that triggering of Fc{gamma}Rs, including Fc{gamma}RIIa, on macrophages or dendritic cells may itself lead to the production of proinflammatory, T cell activating cytokines (43, 44, 51, 52, 53). Presumably, Fc{gamma}RIIa-mediated T cell activation would then be more efficient in individuals with the HH genotype. It should also be noted that Fc{gamma}R triggering by ICs can mitigate the effects of proinflammatory stimuli (54). However, the anti-inflammatory effects of ICs are likely mediated by Fc{gamma}RIIb, an inhibitory Fc{gamma}R present on monocytes, macrophages and dendritic cells (55). In humans, a balance between proinflammatory and anti-inflammatory cytokines is regulated in part by the ratio of activating Fc{gamma}Rs, including Fc{gamma}RIIa, to the inhibitory Fc{gamma}RIIb (44, 55). Given the current lack of mechanistic details, further investigations of the role of Fc{gamma}RIIa in HIV progression are required.

Some studies have found little, if any, anti-gp120 IgG2 (56, 57, 58, 59). In contrast, Scharf et al. found a substantial amount of anti-gp120 IgG2 in IgG from pooled plasma of >100 HIV-infected individuals (60). Although we did not conduct a systematic investigation of IgG2 levels, we did find that eight of eight chronically infected subjects mounted an anti-gp120 IgG2 response, and titers average about 16% of IgG1 titers. The discrepancies between our data and those of others are likely due to differences in methods. Notably, we used anti-subclass mAbs that are considered to be reliable for the detection of IgG1 and IgG2 (61). In any case, it will be of interest to directly determine the role of IgG2 immune complexes in immune activation and CD4+ cell loss during HIV infection.

Because CD4+ cell count is a strong predictor of opportunistic infections and malignancies, we were surprised to find that the development of an AIDS-defining illness was influenced much less by the Fc{gamma}RIIa polymorphism than the progression to a low CD4+ cell count. This observation was explained by demonstrating a protective effect of the RR genotype, relative to the HH genotype, on the incidence of P. jiroveci pneumonias, an AIDS-defining illness. The genotype effect did not extend to the development of P. jiroveci pneumonia subsequent to the AIDS-defining illness. This might be expected based on the importance of a low CD4+ cell count on the incidence of P. jiroveci pneumonia (62, 63) and on our finding of a strong association between the RR genotype and the rate of achieving a CD4+ cell count <200/mm3. Thus, it appears that with respect to PCP, the impact of the RR genotype on CD4+ cell count counterbalanced the effect of the HH genotype.

It is unclear how Fc{gamma}RIIa genotype influences P. jiroveci pneumonia. However, P. jiroveci organisms, when obtained from infected humans, are opsonized with Ab (64). It is possible that exposure to opsonized organisms results in enhanced binding to Fc{gamma}RIIa-bearing cells in the lung and that such binding facilitates infection. However, to our knowledge, type 1 pneumocytes, to which P. jiroveci organisms attach, have not been reported to express Fc{gamma}Rs (65). Alveolar macrophages, in contrast, do express Fc{gamma}RIIa (66), and it is possible that such cells play a role in P. jiroveci infection or pathogenesis.

We found no association between the Fc{gamma}RIIIa polymorphism and HIV progression. We did, however, confirm the results of a previous study that Fc{gamma}RIIIa genotype influenced the risk of KS (36). Our results were somewhat different, however, in that Lehrnbecher et al. found a higher risk of KS among FV heterozygotes, compared with FF homozygotes, but no increased risk among VV homozygotes. This heterozygote disadvantage was not substantiated in our study. Rather, we found a dose response whereby the FF, FV, and VV genotypes were associated with respectively increasing risks. Although the cohorts were different, both studies used specimens exclusively from male subjects who have sex with men and who were exclusively (in the case of the Lehrnbecher et al. study), and predominantly (in our study) white. We suspect that the differences in the two studies are due to chance and that analyzing data from a larger population would provide clarification. Interestingly, an allele dose response very similar to what we demonstrated for HIV-associated KS was also found in women, but not in men, with classical, non-HIV-associated KS (67).

In summary, we have demonstrated a strong association between Fc{gamma}RIIa genotype and progression to a low CD4+ cell count during HIV infection. Individuals with the RR genotype progressed most rapidly, and this relationship was independent of viral load set point. Surprisingly, the Fc{gamma}RIIa genotype had the opposite effect on the development of P. jiroveci pneumonia, with HH homozygotes having the highest risk. Finally, the Fc{gamma}RIIIa gene polymorphism did not predict the rate of HIV progression but was associated with the risk of KS, as reported previously.


   Acknowledgments
 
We acknowledge Joanne Mullen for providing data on MACS participants. Data in this manuscript were collected by the Multicenter AIDS Cohort Study (MACS) with centers (Principal Investigators) at The Johns Hopkins University Bloomberg School of Public Health (Lisa Jacobson, Joseph B. Margolick), Howard Brown Health Center and Northwestern University Medical School (John Phair), University of California, Los Angeles (Roger Detels, Beth Jamieson), and University of Pittsburgh (Charles Rinaldo).


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by funds from the California HIV/AIDS Research Program (formerly the University-wide AIDS Research Program) of the University of California, Grant ID06-I-226. The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute: UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, and UO1-AI-35041. Back

2 Address correspondence and reprint requests to Dr. Donald N. Forthal, 3044 Hewitt Hall, University of California, Irvine, CA 92697. E-mail address: dnfortha{at}uci.edu Back

3 Abbreviations used in this paper: MACS, Multicenter AIDS Cohort Study; CI, confidence interval; OR, odds ratio; IC, immune complexes; KS, Kaposi’s sarcoma. Back

Received for publication July 24, 2007. Accepted for publication September 6, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 

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