Reduction of HIV-1 load in semen during follow-up study of RV144 vaccine trial boosts interest for novel correlates of immune protection in genital mucosa.

The design and production of effective vaccines against human immunodeficiency virus type 1 (HIV-1) are persisting major challenges for the HIV-1 scientific community. It also remains unclear which immune correlates should be considered as part of a successful HIV-1 vaccine and in which tissues these correlates should be measured. The discussion, which has been ongoing for the 30 years since HIV was isolated, is whether a potentially successful HIV1 vaccine should lead to sterilizing immunity against the virus or whether a vaccine would be considered successful if the clinical syndromes linked to the infection were milder or delayed. The RV144 trial conducted in Thailand, using the combination of AIDSVAX B/E gp120 vaccine and the CD4 T-cell– stimulating ALVAC canarypox vaccine, demonstrated an estimated efficacy of 31.2% for protection against acquisition of HIV-1 [1]. Analyses conducted to define RV144 vaccine immune correlates of protection suggested that serum antibodies specific for the V1/V2 regions of the gp120 HIV-1 protein were associated with protection against HIV-1 acquisition [2]. On the contrary, high concentrations of HIV-1 Env-specific immunoglobulin (Ig) A in plasma were directly correlated with infection risk [2]. Hence, these in vivo findings obtained from a human vaccination study clearly illustrate that certain HIV-1–specific antibodies may not be beneficial in preventing HIV-1 acquisition [3], warranting further studies to map the specificity and property of antibodies protecting from, or enhancing, HIV-1 infection and of antibodies that may mitigate the effects of protective antibodies. In the study by Rerks-Ngarm and collaborators in the present issue of The Journal of Infectious Diseases [4], the investigators extended the virologic, immunologic, and clinical course studies of volunteers (receiving either placebo [n = 65] or HIV-1 vaccine [n = 49]) who acquired HIV-1 infection during the RV144 trial, with the aim of determining whether vaccination influenced disease progression linked to HIV-1 infection. High concentrations of specific plasma antibodies are often correlates of protection against acquisition of pathogens for most licensed vaccines [5, 6], and in the RV144 trial the fact that the presence of serum V1/V2 antibodies in vaccinated subjects protected from infection points in the same direction [2]. Whereas the role of humoral immunity on disease progression in HIV-1 infection can be questioned [7–9], control of viremia has often been associated with functional CD8 T cells [10]. Nevertheless, because passive transfer of broadly reactive HIV1 neutralizing antibodies can protect macaques against simian-human immunodeficiency virus infection [11–19], the induction of HIV-1 neutralizing antibodies through HIV-1 vaccination remains a highly desirable goal [20]. In the extended follow-up RV152 study reported by Rerks-Ngarm et al, 61 different end points were studied, including both humoral and cellular responses, during a follow-up of 66 months after the estimated time of HIV-1 acquisition. Unfortunately, the ALVAC-HIV and AIDSVAX vaccination did not significantly affect the clinical course of HIV-1 disease, even when the follow-up was extended to 66 months. However, a tendency for lower viral load in plasma and higher blood CD4 T-cell counts appearing late, at 60 and 66 months after infection, was reported. It will be important to follow the analyses of the cellular immune responses that developed in the Received and accepted 22 May 2012; electronically published 24 July 2012. Correspondence: Francesca Chiodi, PhD, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels väg 16, S-17177 Stockholm, Sweden (francesca. chiodi@ki.se). The Journal of Infectious Diseases 2013;207:1189–92 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail:journals. permissions@oup.com. DOI: 10.1093/infdis/jis477