Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies

Abstract

Summary The development of the HIV-1/SIV chimeric virus macaque model permits the in-vivo evaluation of anti-HIV-1 envelope glycoprotein immune responses. Using this model, we and others have shown that passively infused antibody can protect against an intravenous challenge. However, HIV-1 is most often transmitted across mucosal surfaces and the intravenous challenge model may not accurately predict the role of antibody in protection against mucosal exposure. After controlling the macaque estrous cycle with progester-one, anti-HIV-1 neutralizing monoclonal antibodies 2F5 and 2G12, and HIV immune globulin were tested. Whereas all 5 control animals displayed high plasma viremia and rapid CD4 cell decline, 14 antibody-treated macaques were either completely protected against infection or against pathogenic manifestations of SHIV-infection. Infusion of all three antibodies together provided the greatest level of protection, but a single MAb, with modest virus neutralizing activity, was also protective. Compared to our prior intravenous challenge study with the same virus and antibodies, it appeared that greater protection was achieved after vaginal challenge. This study demonstrates that antibodies can affect transmission and subsequent disease course after vaginal SHIV-challenge; the data begin to define the type of antibody response that could play a role in protection against mucosal transmission of HIV-1. Since intravenous challenge allows the virus rapid access to CD4+ target cells, it was not clear if similar high levels of antibody would be required to protect against a mucosal challenge. Therefore, using the HIV-1/SIV chimeric virus (SHIV) vaginal challenge model, single, double and triple antibody combinations were tested. Four groups of rhesus macaques were infused with control intravenous immune globulin (IVIG, n = 5), monoclonal antibody (MAb) 2G12 (n = 4), MAbs 2G12 + 2F5 (n = 5) or HIVIG + 2F5 + 2G12 (n = 5). All five IVIG control animals developed high plasma viremia and rapid CD4 cell decline following vaginal exposure to SHIV89.6PD (Fig. 1). In contrast, no SHIV plasma RNA was detected in 8 of 14 animals pretreated with antibody. Virus was also not detected by coculture of peripheral blood mononuclear cells (PBMC), or by coculture, or PCR for viral DNA, from cells of inguinal lymph nodes removed 3 weeks after SHIV challenge (data not shown). In addition, these animals did not seroconvert to a SIV p27 gag antigen. Therefore, these 8 monkeys were considered to be completely protected against infection. By these criteria, complete protection was achieved in 4 of 5 animals in the HIVIG/2F5/2G12 group, 2 of 5 in the 2F5/2G12 group and 2 of 4 in the 2G12 group. These protected monkeys also maintained normal CD4 cell counts. Six antibody-treated monkeys became SHIV-infected and had detectable plasma RNA. Whereas IVIG control animals maintained plasma RNA levels of 105 copies/ml through 22 weeks after challenge, plasma viremia in these antibody-treated animals declined to undetectable, or near undetectable, levels by week 12. None of these six infected monkeys developed the profound loss of CD4 cells that was seen in the five control animals. In summary, this is the first study to directly evaluate the protective effect of HIV-1 specific antibodies using the SHIV-macaque vaginal challenge model. By controlling the macaque estrous cycle, we were able to conduct controlled experiments of passive antibody transfer and vaginal challenge. Our data show that antibodies can confer protection against vaginal exposure to a pathogenic SHIV; if virus transmission occurs, their presence can ameliorate the subsequent pathogenic manifestations of virus infection. Compared to our prior intravenous challenge study with the same virus and antibodies, it appears that greater protection was achieved after vaginal challenge. In both our intravenous and vaginal challenge studies, a single MAb, with modest virus neutralizing activity, provided substantial protection. Since the greatest level of protection occurred when the most potent combination of neutralizing antibodies were used, the data validate that in-vitro neutralization assays with PBMC target cells are one relevant measure of functional antibody activity. Despite its limitations, this animal model likely provides relevant data regarding the level and character of antibody required to confer protection against sexual transmission of HIV-1.