We previously reported that a massive infection and systemic depletion of CD4+ T lymphocytes occurs in rhesus macaques during the initial weeks of acute SHIV infections. Despite this severe insult to the immune system, potent virus-specific CD8+ cytotoxic lymphocyte (CTL) responses are detected contemporaneously with the control of plasma viremia during SHIV infections. Because virus-specific neutralizing antibodies first become demonstrable following the suppression of viremia and the antibody titers measured are quite low, B lymphocytes were not thought to play a major role during the early stages of HIV-1 infection. We have constructed 2 isogenic molecularly cloned SHIVs that differ from one another by 9 amino acids and direct distinct clinical outcomes in inoculated rhesus monkeys. SHIVDH12R-Clone 7, like other highly pathogenic CXCR4-tropic SHIVs, induces rapid and complete depletions of CD4+ T lymphocytes and immunodeficiency. In contrast, macaques inoculated with SHIVDH12R-Clone 8 experience only partial and transient losses of CD4+ T cells, prompt control of their viremia, and no evidence of disease for periods of time extending up to 5 years. The contributions of CD8+ and CD20+ lymphocytes in suppressing the replication of the attenuated SHIVDH12R-Clone 8 and maintaining a prolonged asymptomatic clinical course was assessed by treating animals with monoclonal antibodies that deplete each lymphocyte subset at the time of virus inoculation. The absence of either CD8+ or CD20+ cells during the SHIVDH12R-Clone 8 acute infection resulted in the rapid, complete and irreversible loss of CD4+ T cells, sustained high levels of post-peak plasma viremia, and symptomatic disease in Mamu-A*01 negative Indian rhesus monkeys. In Mamu-A*01 positive animals, however, the aggressive, highly pathogenic phenotype was only observed in macaques depleted of CD8+ cells; SHIVDH12R-Clone 8 was effectively controlled in Mamu-A*01 positive monkeys in the absence of B lymphocytes. Taken together, these results indicate that both CD8+ and CD20+ B cells contribute to the control of primate lentiviral infection in Mamu-A*01 negative macaques. Furthermore, the MHC genotype of an infected animal, as exemplified by the Mamu-A*01 allele in this study, has the additional capacity to shift the balance of the composite immune response.[unreadable] [unreadable] Neutralization resistant variants of HIV and SIV arise during the course of infection. We have monitored the sensitivity of viruses, which emerge following SHIV infections of rhesus monkeys and observed a common pattern of resistance to neutralizing antibodies in an intensively studied group of 4 infected animals. These alterations in the virus consisted of insertions and deletions of blocks of 6 or 9 amino acid segments in the V1 and V4 regions of gp120, respectively. Prototype viruses were constructed containing combinations of the repeating units and their effect on virus replication and sensitivity to neutralization was monitored. Our results demonstrate that a cooperativity between variable loops (viz. V1-2 and V4) of gp120 drives the emergence of resistance to neutralizing antibodies. Blocks of amino acids/glycosylation sites inserted or removed from one variable region of gp120 can affect the structure and function of another (and non-contiguous) variable region. This ?cross-talk? between gp120 variable domains may play a major role in evading control by neutralizing antibodies and must be considered in the development of an effective prophylactic vaccine.