The reasons why some individuals can engage in repeated high-risk sexual and drug-injecting activities without ever becoming HIV-positive have long eluded researchers. Several genetic and immunologic factors may come into play. Genetic defects in the cell receptors (the 32 unit deletion in the gene for the CCR5 chemokine receptor) that HIV uses when fusing with uninfected cells is a key to the HIV resistance in some, but by no means all, such persons. Previous studies looking at the immune defenses in these so-called exposed-but-uninfected individuals (EUs) have examined HIV-specific antibodies and, especially, anti-HIV cytotoxic T-lymphocytes (CTLs -- CD8 cells that kill virally infected cells). Last winter, one research group reported finding anti-HIV CTLs and the remnants of aborted infection in many EUs (Treatment Issues, February 1999, pages 1-2). Another recent report describes yet another mechanism for protecting HIV-exposed individuals from infection (see S.A. Stranford et al., Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):1030-5).
Researchers studied a total of 60 persons from four different EU cohorts. The cohorts comprised a diverse population: 63% Caucasian, 31% African-American and 6% Hispanic as well as 35% female. All participants reported regular, unprotected sexual contact with HIV-positive partners. Two individuals also shared syringes with HIV-positive persons. All 60 had remained HIV-negative and had no HIV-specific antibodies in their blood. Only 56% were also negative for anti-HIV antibodies in their urine, indicating that contact with HIV had been sufficient to provoke mucosal membrane antiviral immune activity in some.
The vast majority of the people studied (58 of 60) lacked the CCR5 deletion mutation. CD4 cells from eight randomly selected EUs and four unexposed controls were equally susceptible in lab tests to infection by HIV isolates, including those taken from sexual partners. Anti-HIV CTLs did not seem to be playing a decisive role in preventing HIV replication, either. In one subgroup, 14 of 15 people had no sign of an anti-HIV CTL response.
One mechanism that affords protection from disease progression in HIV-infected individuals is a strong non-cell-killing anti-HIV CD8 cell response that suppresses HIV replication by means of an as yet unidentified secreted factor. Almost half (46%) of EU study participants exhibited enhanced CD8 cell suppression of HIV replication compared to unexposed controls during laboratory cell culture tests. CD8 suppressor activity was confirmed when protection was abrogated by excluding CD8 cells from the assay cultures.
Since immune responses follow exposure to foreign antigens, the researchers classified EU participants according to their HIV exposure history: very high, moderate and low risk (multiple exposures in the past six months, between six months and a year, and greater than a year, respectively). Higher HIV exposure category correlated with increased suppression of the HIV isolates tested. The researchers argued that regular exposure to HIV enhanced antiviral immunity in the EU cohort members, in a fashion comparable to a booster vaccine.