Heterosexual transmission of human immunodeficiency virus type 1 (HIV-1) has dominated the spread of the HIV pandemic. Recent research has focused on the apparent resistance of some highly exposed but still HIV-negative persons [1–5]. Understanding effective resistance mechanisms is crucial for designing preventive measures and determining which vaccine candidates warrant intensive testing. Longitudinal cohort studies have implicated cofactors—symptomatic sexually transmitted diseases (STDs) [6–8] and virus load of the donor [9–11], in particular—in the transmission of HIV by sexual contact. It remains unclear why some persons remain uninfected despite repeated exposure. In various studies, resistance has been attributed, in part, to noncytotoxic CD8 cell responses [12–14], β-chemokines [15], intrinsic CD4 cell resistance [16], cytotoxic T lymphocyte (CTL) activity [1, 5, 17–19], neutralizing antibody to coreceptor molecules [20], viral phenotype [21], or mucosal antibody [22, 23]. Thus far, studies have focused mainly on one or two putative mechanisms at a time. As evidence mounts that a combination of factors may be involved in nontransmission [24], a more comprehensive picture of resistance potential is needed for vaccine testing. Previously, we studied 212 discordant couples (where one partner was HIV positive and the other was HIV negative) in stable heterosexual relationships and compared them with 68 concordant couples (where both were HIV positive) for whom the direction of spread of the virus could be inferred. The following variables correlated significantly with discordance (nontransmission): higher CD8 cell counts and, to a lesser extent, lower plasma virus levels in the HIV-positive partner [25], less anal intercourse [26], and less frequent evidence (by serum antibody) of infection with herpes simplex virus type 2 (HSV-2) and Mycoplasma genitalium [27]. This report focuses on a small group of highly exposed uninfected (EU) women and, when available, their HIV-positive male partners. The cohort was studied intensively by sharing specimens with multiple laboratories to evaluate the potential role of the following factors: CD8 cell noncytotoxic activity, CD8 cell chemokine production, mucosal antibody, CD4 cell coreceptor mutations, CD4 cell proliferative response, neutralizing antibody, and CTL responses. CD8 cell anti-HIV activity of the male partners also was evaluated. The goal was to establish resistance profiles and to determine whether there appeared to be more than one profile. On the basis of findings in our prior studies, we hypothesized that there would be a single resistance pattern of CD8 cell functional activities in both the HIV-positive men and their HIV-negative female partners.
