CD8(+) T cell-mediated suppressive activity inhibits HIV-1 after virus entry with kinetics indicating effects on virus gene expression

Individuals infected with HIV-1 have varying rates of progression to AIDS. Cellular immune responses, comprised of cytolytic and noncytolytic CD8(+) T cell effector functions, are considered important for controlling viremia and maintaining the clinically asymptomatic state. Although there is genera l agreement regarding CD8(+) T lymphocyte cytotoxic functions, considerable controversy exists over the nature of the noncytolytic antiviral activity of CD8(+) cells. The discovery that RANTES (regulated on activation, normal T cell expressed and secreted), MIP-1 alpha, and MIP-1 beta (macrophage in flammatory protein 1 alpha and beta) could inhibit HIV-1 replication by blo cking viral entry processes led to the notion that these molecules are resp onsible for the CD8(+) cell suppressive activity. However, T tropic HIV iso lates requiring the CXCR4 coreceptor for entry are insensitive to the antiv iral effects of these beta-chemokines. Using a CXCR4-dependent virus, we de termined that the mechanism of CD8(+) T cell-mediated activity did act afte r viral entry into the host cell. We also define the kinetics of the HIV li fe cycle in primary activated human CD4(+)-enriched T cells by using an HIV -1 reporter virus system pseudotyped with the CXCR4-dependent HIV-1 envelop e gene of NL4-3, Analysis of these kinetic data indicates that CD8(+) T cel l-mediated suppressive activity acts at a stage in the viral life cycle aft er entry and independently of the HIV envelope. Additionally, we show that the antiviral activity targets stages of the virus life cycle correlating w ith transcription and early proviral gene expression, These findings not on ly provide a range of possible targets for the CD8(+) T cell-mediated activ ity but also support the notion that this antiviral activity is multifactor ial in nature.