HIV This Week

Effective, low-titre antibody protection against low-dose repeated mucosal SHIV challenge in macaques.

Hessell AJ, Poignard P, Hunter M, Hangartner L, Tehrani DM, Bleeker WK, Parren PW, Marx PA, Burton DR. Nat Med. 2009 15(8):951-4.

Neutralizing antibodies are thought to be crucial for HIV vaccine protection, but studies in animal models suggest that high antibody concentrations are required. This is a major potential hurdle for vaccine design. However, these studies typically apply a large virus inoculum to ensure infection in control animals in single-challenge experiments. In contrast, most human infection via sexual encounter probably involves repeated exposures to much lower doses of virus. Therefore, animal studies may have provided an overestimate of the levels of antibodies required for protection in humans. The authors investigated whether plasma concentrations of antibody corresponding to relatively modest neutralization titres in vitro could protect macaques from repeated intravaginal exposure to low doses of a simian immunodeficiency virus-HIV chimera (SHIV) that uses the CC chemokine receptor 5 (CCR5) co-receptor. An effector function-deficient variant of the neutralizing antibody was also included. The results show that a substantially larger number of challenges is required to infect macaques treated with neutralizing antibody than control antibody-treated macaques, and support the notion that effector function may contribute to antibody protection. Overall, the results imply that lower amounts of antibody than previously considered protective may provide benefit in the context of typical human exposure to HIV-1.

For abstract access click here: 1

Editors’ note: This study, as in virtually all similar studies published to date, used viruses matched to the neutralising antibody tested. Thus, it is unclear whether this strategy would protect against a variety of circulating viruses. Nonetheless, it is tantalising to think that this macaque study using low dose viral challenges that better reflect repeated human mucosal exposure to low numbers of virus particles may in some way help us to understand the results of the RV144 Thai vaccine trial in which low risk participants may have been better protected. We await with anticipation further results of that trial over the coming months.

Manrique M, Kozlowski P, Wang SW, Wilson R, Micewicz E, Montefiori D, Mansfield K, Carville A, Aldovini A. Mucosal Immunol. 2009; 2:536-50.

Preventive human immunodeficiency virus (HIV) vaccination may require induction of virus-specific immune responses at mucosal sites to contain viral infection locally after exposure, as most HIV infections occur through mucosal surfaces. The authors compared the efficacy of an intranasal or intramuscular Simian immunodeficiency virus (SIV)+ interleukin (IL)-2+IL-15 DNA/SIV-MVA (modified vaccinia virus Ankara) vaccination in preventing disease progression in SIVmac251 intrarectally challenged rhesus macaques. SIV-specific rectal IgA responses were more significantly persistent in nasally vaccinated than in intramuscularly vaccinated animals. No significant differences were observed in the magnitude of systemic T-cell responses between the two groups, although the nasal immunization induced more significant anti-SIV T-cell responses in the colorectal mucosa. After challenge, CD4(+) central memory (C(M)) T-cell preservation and significant disease-delay were observed in both vaccination groups. However, nasally vaccinated animals had more significant early preservation of circulating and colorectal CD4(+) C(M) T cells, of circulating CD4(+)/alpha4beta7(+) effector memory (E(M)) T cells, and a longer disease-free interval when compared with the intramuscularly vaccinated or control groups. Regardless of vaccination status, long-term viraemia control and preservation of CD4(+) C(M) T cells was detected in animals with significantly higher systemic CD8(+)/tumour necrosis factor (TNF)-alpha(+) and CD8(+)/interferon (IFN)-gamma(+) T-cell responses and higher SIV-specific CD4(+)/IL-2(+) responses in colorectal T cells.

For Abstract click here: 1

Editors’ note: Can you imagine taking a vaccine nasally? In this study, nasal vaccination provided more significant protection from progression to AIDS than classical intramuscular vaccination. It is possible that different mucosal routes will provide different degrees of protection. One thing to aim for would be lower viral loads in the gut in acute infection so that there would be less antigen driving immune activation, our antibody response to HIV. A vaccine that did not prevent HIV infection but that would delay the onset of disease by limiting viral replication from the start would be a welcome addition.