EVIDENCE FOR THE HIV-1 PHENOTYPE SWITCH AS A CAUSAL FACTOR IN ACQUIRED IMMUNODEFICIENCY

Both cellular and humoral immunodeficiency develop in vivo after prolo nged infection with HIV-1, but the mechanisms are unclear(1). Initial infection with HIV-1 is transmitted by macrophage (M)-tropic/non-syncy tia-inducing (NSI) viruses(2,3), which hyperactivate the immune system (4,5), and, in one view, cause immunodeficiency by ''exhaustion''(4,6) of lymphoid tissue. An alternative hypothesis is that immunodeficienc y is caused by the replacement of M-tropic viruses by T cell (T)-tropi c/syncytia-inducing (SI) viruses, which are known to be highly cytopat hic in vitro and emerge late in infected individuals around the time o f transition to AIDS (refs. 1, 7-9). To test these two possibilities, we have developed an ex vivo model of humoral immunity to recall antig ens using human lymphoid tissue. This tissue supports productive infec tion with both M-and T-tropic HIV-1 isolates when cultured ex vivo(10, 11). We found that specific immune responses were enhanced by producti ve infection of the tissue with M-tropic/NSI HIV-1 isolates, but were blocked by T-tropic/SI HIV-1 isolates. The mechanism involves specific irreversible effect on B-cell activity. Our results support the hypot hesis that the phenotype switch to T-tropic viruses is a key determina nt of acquired humoral immunodeficiency in patients infected with HIV.