The first observation of host anti-HIV activity was made soon after HIV was identified. CD8+ cells were found to suppress HIV replication without killing the infected cells. This finding uncovered a novel CD8+ cell noncytotoxic anti-HIV response (CNAR) that was distinct from the classic cytotoxic T-cell activity. CNAR is mediated by a soluble secreted component, the CD8+ cell anti-HIV factor (CAF), that differs from other cytokines. CNAR/CAF has been shown to block HIV transcription, perhaps by limiting the effect of the transcription elongation factor P-TEFb. Because CNAR appears during early primary infection and suppresses all HIV-1 and HIV-2 isolates via secretion of CAF, it has features of an innate immune response. Healthy asymptomatic individuals, particularly LTSs, exhibit increased frequencies of the CD8+ cells that mediate CNAR in comparison to those who progress to AIDS. Moreover, studies of SIV-infected rhesus monkeys depleted of CD8+ cells in vivo suggest that the virus level is maintained by a CD8+ cell noncytotoxic process. Also, CNAR appears to protect HESNs from infection via sexual contact and children born to infected mothers.

Studies of CAF have uncovered a variety of other soluble factors that can inhibit HIV replication. These include the β-chemokines that are the natural ligands for CCR5 and therefore compete with HIV (R5) for binding and entry into the cell. Their recognition led to the identification of the most prominent protective factor against HIV infection: homozygosity for a CCR5 allele that encodes a truncated protein