The HIV-1 gp120 V1V2 loop: structure, function and importance for vaccine development

Abstract

Although the second variable loop (V2) of the HIV-1 gp120 envelope glycoprotein shows substantial sequence diversity between strains, its functional importance imposes critical conservation of structure, and within particular microdomains, of sequence. V2 influences HIV-1 viral entry by contributing to trimer stabilization and co-receptor binding. It is one of 4 key domains targeted by the broadly neutralizing antibodies that arise during HIV-1 infection. HIV-1 uses V1V2 sequence variation and glycosylation to escape neutralizing antibody. In the Thai Phase III HIV-1 vaccine trial, RV144, vaccine-induced IgG against V1V2 inversely correlated with the risk of HIV-1 acquisition, and HIV-1 strains infecting RV144 vaccine recipients differed from those infecting placebo recipients in the V2 domain. Similarly, non-human primate challenge studies demonstrated an inverse correlation between vaccine-induced anti-V2 responses and simian immunodeficiency virus acquisition. We hypothesize that increased magnitude, frequency and duration of vaccine-induced anti-V2 antibody responses should improve efficacy afforded by pox-protein prime–boost HIV vaccine strategies.

Keywords::

• efficacy
• gp120
• HIV vaccine
• neutralizing antibodies
• nonneutralizing antibodies
• RV144
• V1V2 loop

Acknowledgements

Figure 1A was kindly provided by Carter Lee, Global Solutions for Infectious Diseases, South San Francisco, CA. The authors thank Ms. Stephanie Stevens from US MHRP for assistance with creation of Figure 1C.

Financial & competing interests disclosure

The authors received funding from the US Army Medical Research and Materiel Command (USAMRMC), and its Cooperative Agreement (DAMD17-98-2-7007) with the Henry M. Jackson Foundation for the Advancement of Military Medicine. The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense or the US Government. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Although the gp120 V2 loop is variable in sequence and length, it possesses important conserved domains.

• The V2 variable loop influences HIV-1 viral entry by contributing to trimer stabilization and coreceptor binding.

• The V2 domain contributes to conformational epitopes targeted by broadly neutralizing antibodies.

• HIV-1 uses V1V2 mutations to escape from neutralization targeted against distant epitopes.

• Nonhuman primate challenge studies have demonstrated an association between vaccine-induced V1V2 antibody responses and protection against virus acquisition.

• Plasma IgG anti-gp70V1V2 antibodies inversely correlated with risk for HIV-1 acquisition in the RV144 human vaccine efficacy trial.

• RV144 vaccinees who became infected with HIV-1 harbored virus that was more likely to differ from vaccine sequences in the V2 domain.

• Increasing magnitude, frequency and duration of vaccine-induced V1V2 antibody responses is an important goal to improve efficacy afforded by pox-protein prime boost HIV vaccine strategies.

Notes