Scientific Publications

Biased enrollment and attrition compromise the power of clinical trials and limit generalizability of findings. We identify predictors of enrollment and retention for HIV-discordant couples enrolled in prospective studies in Zambia.

An AIDS vaccine could play a very significant role in reversing the HIV pandemic, saving millions of lives. For a vaccine to have such an impact, it must be widely available and adopted and taken up rapidly in the countries most affected. A demand-forecasting model provides a valuable tool that can guide R&D spending decisions and identify policy actions to help achieve these goals.

: We describe promotional strategies for couples' voluntary HIV counseling and testing (CVCT) and demographic risk factors for couples in Lusaka, Zambia, where an estimated two thirds of new infections occur in cohabiting couples.

Trimers of the HIV-1 envelope glycoprotein (Env) effectuate viral entry into susceptible cells. Therefore Env trimers are the targets for neutralizing antibodies. This study models the number of trimers required for virion infectivity. It also delineates the minimum number of antibody molecules that would neutralize a virion. First, Env function was assumed to be incremental (all envelope glycoprotein units contribute equally) or liminal (characterized by thresholds). Then, such models were combined and shown to fit published data on phenotypically mixed pseudotype viruses. Virions with 9 trimers would require around a median of 5 of them for strong infectivity; the proportion varies among strains and mutants. In addition, the models account for both liminal and incremental protomeric effects at the trimer level: different inert Env mutants may affect trimer function in different degrees. Because of compensatory effects at the virion and trimer levels, however, current data cannot differentiate between all plausible models. But the biophysically and mathematically rationalized blurring of thresholds yields candidate models that fit different data excellently.

Most new HIV infections in Africa are acquired from cohabiting heterosexual partners. Couples' Voluntary Counselling and Testing (CVCT) is an effective prevention strategy for this group. We present our experience with a community-based program for the promotion of CVCT in Kigali, Rwanda and Lusaka, Zambia.

The role of homosexuality and anal sex practices in the African HIV -1 epidemic is not well described. We aimed to assess the risk factors for prevalent HIV-1 infection among men who have sex with men (MSM) to guide HIV-1 prevention efforts.

The CCR5 co-receptor binds to the HIV-1 gp120 envelope glycoprotein and facilitates HIV-1 entry into cells. Its N terminus is tyrosine-sulfated, as are many antibodies that react with the co-receptor binding site on gp120. We applied nuclear magnetic resonance and crystallographic techniques to analyze the structure of the CCR5 N terminus and that of the tyrosine-sulfated antibody 412d in complex with gp120 and CD4. The conformations of tyrosine-sulfated regions of CCR5 (alpha-helix) and 412d (extended loop) are surprisingly different. Nonetheless, a critical sulfotyrosine on CCR5 and on 412d induces similar structural rearrangements in gp120. These results now provide a framework for understanding HIV-1 interactions with the CCR5 N terminus during viral entry and define a conserved site on gp120, whose recognition of sulfotyrosine engenders posttranslational mimicry by the immune system.

Most successful vaccines elicit neutralizing antibodies and this property is a high priority when developing an HIV vaccine. Indeed, passively administered neutralizing antibodies have been shown to protect against HIV challenge in some of the best available animal models. For example, antibodies given intravenously can protect macaques against intravenous or mucosal SHIV (an HIV/SIV chimaera) challenge and topically applied antibodies can protect macaques against vaginal SHIV challenge. However, the mechanism(s) by which neutralizing antibodies afford protection against HIV is not understood and, in particular, the role of antibody Fc-mediated effector functions is unclear. Here we report that there is a dramatic decrease in the ability of a broadly neutralizing antibody to protect macaques against SHIV challenge when Fc receptor and complement-binding activities are engineered out of the antibody. No loss of antibody protective activity is associated with the elimination of complement binding alone. Our in vivo results are consistent with in vitro assays indicating that interaction of Fc-receptor-bearing effector cells with antibody-complexed infected cells is important in reducing virus yield from infected cells. Overall, the data suggest the potential importance of activity against both infected cells and free virus for effective protection against HIV.

We have identified several patient sera showing potent and broad HIV-1 neutralization. Using antibody adsorption and elution from selected gp120 variants, the neutralizing specificities of the two most broadly reactive sera were mapped to the primary receptor CD4-binding region of HIV-1 gp120. Novel antibodies to the CD4-binding site are elicited in some HIV-1-infected individuals, and new approaches to present this conserved region of gp120 to the immune system may result in improved vaccine immunogens.

This study was conducted to compare viral dynamics in blood and semen between subjects with antibody negative, acute HIV-1 infection and other subjects with later stages of infection.

The identification of cross-neutralizing antibodies to HIV-1 is important for designing antigens aimed at eliciting similar antibodies upon immunization. The monoclonal antibody (mAb) F425-B4e8 had been suggested previously to bind an epitope at the base of V3 and shown to neutralize two primary HIV isolates. Here, we have assessed the neutralization breadth of mAb F425-B4e8 using a 40-member panel of primary HIV-1 and determined the epitope specificity of the mAb. The antibody was able to neutralize 8 clade B viruses (n=16), 1 clade C virus (n=11), and 2 clade D viruses (n=6), thus placing it among the more broadly neutralizing anti-V3 antibodies described so far. Contrary to an initial report, results from our scanning mutagenesis of the V3 region suggest that mAb F425-B4e8 interacts primarily with the crown/tip of V3, notably Ile(309), Arg(315), and Phe(317). Despite the somewhat limited neutralization breadth of mAb F425-B4e8, the results presented here, along with analyses from other cross-neutralizing anti-V3 mAbs, may facilitate the template-based design of antigens that target V3 and permit neutralization of HIV-1 strains in which the V3 region is accessible to antibodies.