Immune responses that correlate with HIV-1 protection?

Despite intense research, there is still no vaccine to prevent HIV infection. Given the difficulties encountered, the identification of the immune correlates of protection is a prerequisite for the development of vaccination protocols to control the HIV epidemic. It would therefore be extremely valuable to conduct extensive investigations of the immune responses elicited in highly exposed, persistently negative (HEPS) individuals, because this minority group appears to resist HIV infection despite repeated exposure, often to many different HIV-infected partners.

Hirbod et al. ^[1] performed a prospective study of a large group of 113 high-risk Kenyan female sex workers (FSW) and analyzed three different markers of HIV-specific immune responses in HEPS individuals: genital IgA and their ability to neutralize primary HIV isolates, HIV-specific interferon gamma (IFNγ) ELISPOT cellular responses, and HIV-specific cellular proliferation in peripheral blood mononuclear cells (PBMC). Among 113 FSW included in the study, 24 acquired HIV between May 1998 and November 2002 and the others remained HIV seronegative. Statistical analysis revealed that the detection of genital HIV-specific neutralizing IgA and systemic proliferative responses in circulating PBMC at enrolment correlated well with not becoming HIV infected; all other variables (including estimates exposure to HIV), except HSV2 (known to be strongly associated with HIV acquisition), were similar for cases and controls. Thus, in this rigorously conducted prospective study, the authors reveal the possible contribution of two independent factors - HIV-specific IgA and proliferative response - to protection against heterosexual transmission.

Could these factors be sufficient for protection? According to Hirbod et al. ^[1], detection of HIV-specific cellular IFNγ ELISPOT in the systemic compartment did not correlate with subsequent resistance to HIV acquisition. However, earlier studies examining the HIV-specific immune response in HEPS groups detected HIV-specific cytotoxic T cells in blood ^[2] and the cervix ^[3]. These studies suggest that additional experimental approaches such as searching for local mucosal cellular responses (HIV-specific cellular IFNγ ELISPOT) and the use of different assays for cytotoxic T-cell detection may help in identifying other correlates of protection.

The presence of IgA has been described in several ^[4] but not all ^[5] HEPS groups. The results reported by Hirbod et al. on the basis of assays performed in a blind protocol lend further support to the notion that neutralizing IgA in the genital track contributes to protection against HIV. The persistence of the immune response in the FSW was not analyzed, so the absence of strict correlation with protection could be due to either the acquisition or loss of the protective immune response with time or the failure of this immune response to protect some individuals. The various studies of HEPS individuals and now this well designed prospective study of FSW by Hirbod et al. ^[1] provide hope that a specific immune response, which may be acquired by regular immune 'boosting' of HIV-specific responses, contributes to protection against HIV infection.

Could other elements of the immune response maximize protection? No HIV-specific IgG was detected in these HEPS individuals ^[4], although they have frequently been found in the genital tract of HIV-infected individuals ^[6]. In an animal model, after passive intravenous transfer of neutralizing IgG, the antibodies could be recovered in the vaginal compartment, as a result of transudation. This passive transfer completely protected macaques from vaginal challenge with SHIV virus ^[7,8]. Recently, we have shown that in addition to neutralizing IgG antibodies, some nonneutralizing HIV-specific IgG efficiently inhibited HIV replication in vitro in immature dendritic cells and macrophages. IgG protects these antigen-presenting cells from infection by two mechanisms: classical neutralization of HIV infectivity mediated by the antibody Fab domain (and also detected on CD4+ T lymphocytes) and inhibition associated with binding of the HIV-specific antibody to Fcγ I and II receptors at the surface of macrophages and dendritic cells, respectively ^[9]. These results suggest that the presence of additional nonneutralizing antibodies may reduce the amount of neutralizing antibodies required to protect macrophages and dendritic cells in the mucosal compartment where these cells reside. Moreover, a recent in-vivo study by Burton and his group provides further evidence for the role of the Fcγ part of IgG in the mechanism of protection against HIV. They found that, in contrast to the neutralizing monoclonal antibody IgG1 b12, passive transfer of a mutated form of b12 (L234A, L235A) unable to bind to Fc receptors, protected macaques less well against vaginal challenge with SHIV ^[10]. This group proposed that antibody-dependent cellular cytotoxicity (ADCC), involving FcγR III, participates in the protection against HIV conferred by the neutralizing monoclonal antibody b12. Therefore, using vaccination to induce a strong IgA and IgG HIV-specific immune response, including both neutralizing and nonneutralizing inhibitory antibodies directed at mucosal sites, may be of great additional value for protection.

Substantial efforts are now being made to find out how to induce an efficient immune response directly at the mucosa sites where HIV infection takes place. The genital mucosa is often the first portal of HIV entry, but recent findings indicate that the gastrointestinal track is a major site of HIV replication and of massive early T-cell death. Each of the mucosa has their own characteristics in term of morphology, immune cell organization, gender disparity and immune responses generated. It is therefore now a priority to elucidate the immune response, HIV-1 entry and infection mechanisms, in these mucosa.

It seems that to be effective for all people at risk, any vaccine designed to prevent mucosal HIV infection will need to generate efficient secreted (and serum) antibodies that can block HIV entry in all these mucosal epithelial barriers. With these humoral responses, strong cellular responses comprising proliferating T-cell responses and cytotoxic T-cell induction might be highly beneficial for clearance of mucosal infection and prevention of systemic spread.