HIV-1 gp120-directed antibody-dependent cellular cytotoxicity (ADCC) is one of several possible mechanisms of CD4 cell destruction in HIV-1 disease. Clinical studies suggest that gp120-directed ADCC is a major determinant of the rate of CD4 percentage decline in peripheral blood over time. This CD4 cell destruction presumably takes place in lymphoid tissues, and recent studies have suggested that, in both HIV and SIV, gut- associated lymphoid tissue (GALT) is a major site of both viral replication and CD4 cell destruction. In preliminary studies, we have shown that granzyme B+ NK cells are abundant in lymph nodes from HIV-infected patients, in a distribution similar to that of apoptotic cells in some patients. Since, in vitro HIV-1 gp120- specific ADCC mediates death of gp120-bearing CD4+ target cells via apoptosis, we postulate that NK cells, via ADCC, are the predominant effector cell that mediates CD4 cell destruction in the lymph nodes and GALT. In this proposal, archived GALT and LN specimens and GALT and lymph nodes tissues from prospectively enrolled HIV-infected volunteers for rectal biopsy and lymph node biopsy, respectively, will be evaluated for the frequency and distribution pattern of NK cells, apoptotic cells, CD4 and CD8 lymphocyte subsets, HIV-1 RNA by in situ hybridization and expression of HIV-1 gp120, gp41 and p24 antigens. Cytolytic potential of NK cells in the lymph node will be evaluated by determining FcgammaRIIIA genotype, expression of perforin and granzyme B, and the ability to mediate HIV-1 directed ADCC in vitro. These data will be evaluated in order to form and test hypotheses regarding the relationship between CD4 cell destruction in lymphoid tissue (measured by CD4+ cell depletion and apoptosis), HIV-1 RNA and antigen expression (measured by in situ hybridization and the expression of p24, gp120 and gp41), the presence of NK cells in lymphoid tissues (measured as CD16+, CD56+, CD57+ and/or CD94+ cells), the cytolytic potential of CD16+ and CD8+ cells (measured by expression of granzyme B and perforin) and the ADCC-mediating capacity of NK cells (measured by K562 lysis, gp120-specific ADCC activity and FcgammaRIIIA genotype). These relationships will be evaluated in the context of the clinical status of each patient group to be studied, and in comparison to HIV-uninfected subjects.
