Persistence of HIV-1 despite highly active antiretroviral therapy (HAART) and immune responses: Evidence for a novel viral reservoir in patients on HAART and characterization of HIV-1 virus and immune responses in elite suppressors

Persistence of HIV-1 despite highly active antiretroviral therapy (HAART) and robust immune responses is a major obstacle to eradication of viral infection. Moreover, poor understanding of immune responses capable of suppressing HIV-1 viremia has slowed development of an effective vaccine against the virus. Therefore, we have studied residual viremia in patients on effective HAART and characterized virus and immune responses in elite suppressors (ES) who control viral replication to less than 50 copies/ml of plasma without antiviral therapy.; Antiretroviral therapy can reduce HIV-1 viremia to below the detection limit of ultrasensitive clinical assays (50 copies HIV-1 RNA/ml). However, latent HIV-1 persists in resting CD4+ T cells, and low residual levels of free virus are found in the plasma of patients on HAART. Using intensive sampling, we analyzed residual viremia and compared these viruses to latent proviruses in resting CD4+ T cells. Despite the large diversity of pol sequences in resting CD4+ T cells, the residual viremia was dominated by a homogeneous population of viruses with identical pol and env sequences that was rarely found in resting CD4+ T cells. This population persisted in the plasma of some patients without evolution for months to years. The unique characteristics of this plasma virus suggest that it is not the product of ongoing viral replication and it may be released from a viral reservoir other than circulating CD4+ T cells.; We have also found the first direct evidence that most ES experience chronic low level viremia and investigated the extent and impact of CTL escape mutations in HLA-B*57+ ES. Mutations in HLA-B*57-restricted Gag epitopes were present in all viruses from plasma of these individuals but were rare in proviruses, suggesting powerful selective pressure acting at these epitopes. Surprisingly, CD8+ T cell interferon-gamma responses were detected against some mutant epitopes found in plasma virus suggesting the development of de novo responses to viral variants. In all individuals, relative CD8+ T cell interleukin-2 responses showed good correlation with the selection observed in vivo. Continued viral suppression probably reflects CTL responses against unmutated epitopes and residual or de novo responses against epitopes with escape mutations.; Little is known about the role of neutralizing antibody in patients on effective HAART and in Elite Suppressors. We analyzed full-length env sequences from plasma virus and from provirus in resting CD4 + T cells of HAART-treated patients, Elite Suppressors, and untreated HIV-1-infected patients with progressive disease. For each patient group, we assessed plasma virus neutralization by autologous, contemporaneous plasma. Both Elite Suppressors and HAART-treated patients had lower titers of nAb against HIV-1 lab strains than untreated viremic patients. Surprisingly, nAb titers against autologous, contemporaneous plasma viruses were similarly low in chronic progressors, Elite Suppressors, and HAART-treated patients. In Elite Suppressors and HAART-treated patients, nAb titers against autologous plasma viruses also did not differ significantly from titers against autologous proviruses from resting CD4+ T cells. These results suggest that high titer nAb are not required for maintenance of viral suppression in Elite Suppressors and that nAb do not select plasma virus variants in most HAART-treated patients.; Though our work has suggested that CD8+ T cell responses are critical for suppression of viremia in ES, it is also possible that ES are infected with defective viruses. We isolated and characterized fully replication competent virus from an HLA-B*5703+ male who controlled viral replication to undetectable levels shortly after seroconversion. Virologic breakthrough eventually occurred and was associated temporally with the development of CTL escape mutations in two targeted HLA-B*57-restricted epitopes in Gag. Virus isolated after a nearly 3 log incre...