Background: Truly non-progressive HIV-infected individuals comprise of only 0.8% of total HIV-infected population. These individuals have undetectable plasma viremia, high CD4⁺ and CD8⁺ T-cell counts, strong immune responses and remain therapy naive. Here we have studied one such rare individual who displays strong anti-HIV immunity. Such individuals may harbor clues to natural control of HIV.

Methods: PCR amplification of viral sequences over 8 yrs and sequence of full-length HIV genomes for the last 4 yrs. Methods used were electron microscopy, non-cytolytic CD8 antiviral activity determination using transwell system, quantitation of chemokines and cytokines by ELISA, antibody blocking assays for cytokines and chemokines, lymphocyte immunophenotyping, flow cytometry, lymphocyte proliferation responses to HIV specific antigens, and HIV-specific CD8⁺ T-cell responses using ELISpot assay.

Results: We identified a non-evolving replication-incompetent HIV-1 strains characterized by stop codons in the gag gene from a truly non-progressive individual. Potent immune responses against HIV-1 were observed in his PBMC, despite lack of viral replication for the least 8 yrs. In addition, non-cytolytic CD8⁺ T-cell activity was shown to protect his PBMC from productive infection by HIV-1 strains. Although several Chemokines, cytokines/IFN-g were produced by his CD8⁺ T-cells, none had any antiviral role. This antiviral activity was a memory response, induced by HIV-specific stimulation, at similar levels observed by PHA-stimulation, but was absent in ex vivo resting T-cells. Immunological mechanisms associated with this antiviral suppressive activity included vigorous Gag-specific helper T-cell proliferative responses, and high-level HIV-specific IFN-g release by both CD4⁺ and CD8⁺ T-cells. These responses were broadly directed against multiple Gag epitopes (some novel and some known epitopes). The majority of responses to these peptides were mediated by CD4⁺ T-cells, which supported that cytolytic activity was minimal in this individual. Strong HIV-specific helper T-cell function was also associated with strong neutralizing antibodies.

Conclusions: This individual provides a model for how innate immunity against HIV can be sustained in the absence of replicating virus. Understanding how to induce these protective immune responses in other individuals could provide a major step forward in the design of effective immunotherapies or vaccines against HIV infection.