AIDSWEEKLY Plus; Monday, February 8, 1999
Daniel J. DeNoon, Senior Editor

Jay A. Levy and colleagues at the University of California, San Francisco, have shown that a soluble factor produced by the CD8(+) T cells can inhibit HIV infection of CD4(+) T cells. Such activity is particularly strong in people who remain asymptomatic despite long-term HIV infection.

Now Sharon A. Stranford, Levy, and colleagues have found that people resistant to HIV infection are like the long-term asymptomatics.

"The observed strong noncytopathic CD8(+) cell anti-HIV response may be an antiviral immune activity contributing to the apparent protection from infection in these exposed uninfected individuals," Stranford et al. reported in the Proceedings of the National Academy of Sciences ("Lack of Infection in HIV Exposed Individuals Is Associated with A Strong CD8(+) Cell Noncytotoxic Anti-HIV Response," Proc Natl Acad Sci U S A 1999 Feb 2;96(3):1030-5).

Stranford et al. studied 60 men and women with repeated receptive vaginal or rectal sexual exposure to HIV infected partners. Two of these exposed uninfected (EU) individuals also shared hypodermic needles. All 60 subjects remained HIV uninfected as demonstrated by antibody tests, coculture analysis, and in many cases polymerase chain reaction (PCR) analysis of peripheral blood mononuclear cells (PBMC).

Their resistance wasn't due to the uninfectability of their CD4(+) cells. CD4(+) cells from eight randomly selected EUs showed no difference from unexposed controls to susceptibility to in vitro HIV infection. In an unprecedented additional study, CD4(+) cells from five EUs were cultured with HIV isolated from their sex partners. All were as susceptible to virus infection as unexposed controls.

And protection wasn't due to lack of sufficient virus in the infected partners: infectious virus, albeit of the non-syncytium- inducing (NSI) phenotype, could be cultured from most of these men. And a majority had detectable HIV in their seminal fluid.

When tested against SF33 - a highly pathogenic, fast-replicating, and (beta)-chemokine-insensitive HIV-1 strain - 45 percent of the 35 subjects tested had greater CD8(+) noncytopathic HIV suppression than unexposed controls (n=20).

When tested against weaker strains of HIV that more closely resembled the strains to which they were likely to have been exposed, 83 percent of 15 EUs and 72 percent of 25 EUs showed strong inhibition of a (beta)-chemokine-sensitive primary HIV-1 isolate or a (beta)- chemokine-resistant SF2 HIV-1 strain, respectively.

Two of the study subjects had the homozygous delta32 CCR5 mutation associated with HIV resistance. One of these subjects was included in the infectivity analyses and showed strong noncytopathic CD8(+) responses to SF33 and SF2.

When cohort members were sorted according to level of exposure, Stranford et al. found that strong CD8(+) anti-HIV activity was far more likely in those whose most recent exposure to HIV occurred within a year of testing.

"This finding strongly suggests that exposure to HIV is needed for the induction of this immune activity and may indicate that the recall of this immune response is limited in duration," they wrote. "Subsequent exposures to HIV may act to enhance or expand this immune function."

In a final series of experiments, the researchers exposed the PBMC of the EUs to in vitro challenge with HIV-1[SF2]. PBMC from EUs with strong CD8(+) anti-HIV activity had very low levels of HIV replication, while PBMC from EUs lacking the antiviral action permitted HIV replication at the same level as that seen with unexposed controls.

Removal of CD8(+) from these cell cultures ended the anti-HIV effect.

"The discovery of this immunologic correlate to protection is encouraging for the future design of anti-HIV vaccines and could be used for the evaluation of vaccine preparations likely to induce protective immunity," Stranford et al. concluded.

The Levy team has in the past demonstrated several principal characteristics of CD8(+) noncytopathic suppression of HIV:

• It does not involve the destruction of target cells.
• It does not modulate the activation of target CD4+ cells.
• Its effector phase is independent of major histocompatibility complex (MHC) restriction. The strength of the activity is dependent on the genetic relatedness between the effector and target cells, but not necessarily on HLA class I or class II determinants.
• It is at least in part mediated by a novel soluble factor not identical to any other known cytokines or chemokines.

The last of these findings has been controversial as CD8+ T-cell- mediated suppression of HIV has been linked to the cells' expression of the anti-HIV (beta)-chemokines RANTES, MIP-1(alpha) and MIP-1(beta) (Cocchi et al., Science 1995 Dec 15;270(5243):1811-5), and the C-X-C chemokine SDF- 1.

But while acknowledging the contribution made by (beta) chemokines, Levy and co-workers are convinced that the inhibitory activity they describe is due mainly to a long-sought, as-yet- unidentified substance they have dubbed CD8+ cell antiviral factor or CAF (for an account of the CAF/chemokine debate between the Levy and Robert Gallo camps see AIDS Weekly Plus, December 23/30, 1996).

These studies were supported by grants from the California State University-wide AIDS Research Program and the National Institutes of Health.

The corresponding author for this study is Jay A. Levy, Department of Medicine, University of California, San Francisco, CA 94143-1270. Email: <jalevy@itsa.ucsf.edu>.

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