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HIV-1 Does Not Provoke Alteration of Cytokine Gene Expression in Lymphoid Tissue after Acute Infection Ex Vivo¹

Annette Audigé^2,*, Erika Schlaepfer^*, Athos Bonanomi, Helene Joller, Marlyse C. Knuchel^3,*, Markus Weber, David Nadal and Roberto F. Speck^2,*

^* Division of Infectious Diseases and Hospital Epidemiology, Institute of Clinical Immunology, and Clinic of Visceral and Transplantation Surgery, University Hospital of Zurich, and Division of Infectious Diseases, University Children’s Hospital of Zurich, Zurich, Switzerland

The cytokine response to invading microorganisms is critical for priming the adaptive immune response. During acute HIV infection, the response is disrupted, but the mechanism is poorly understood. We examined the cytokine response in human lymphoid tissue, acutely infected ex vivo with HIV. Lymphoid tissue was cultured either as blocks or as human lymphocyte aggregate cultures (HLAC) of tonsils and lymph nodes. This approach allowed us to examine the effects of HIV on cytokines using distinct culture techniques. In contrast to HLAC, mock-infected tissue blocks displayed a 50- to 100-fold up-regulation of mRNAs for IL-1, -6, and -8 in the first 6 days of culture. Parallel increases were also noted at the protein level in the supernatants. Although IL-1, -6, and -8 are known to synergistically enhance HIV replication, peak HIV replication (measured as p24 Ag) was similar in tissue blocks and HLAC. Surprisingly, vigorous HIV replication of CXCR4- and CCR5-tropic HIV strains did not result in characteristic mRNA profiles for IL-1, -2, -4, -6, -8, -10, -12, -15, IFN-, TNF-, TGF-, and -chemokines in tissue blocks or HLAC. The increased expression of IL-1, -6, and -8 in tissue blocks may approximate clinical situations with heightened immune activation; neutralization of these cytokines resulted in inhibition of HIV replication, suggesting that these cytokines may contribute to HIV replication in certain clinical settings. These results also indicate that different molecular mechanisms govern HIV replication in tissue blocks and HLAC. Prevention of effective cytokine responses may be an important mechanism that HIV uses during acute infection.

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