The Search for an HIV Vaccine: Utilizing Non-human Primates and SIV

On June 5, 1981, the U.S. CDC published a Morbidity and Mortality Weekly Report. In this report detailed five different cases of a rare lung infection, Pneumocystis carinii, in previously healthy young males, indicating severe immune deficiency. By the end of the year, there are over 270 reported cases of similar immune deficiency among young men. This immune deficiency would quickly be identified as the ultimately fatal  Human Immunodeficiency virus.

The Human Immunodeficiency virus (HIV) is a retrovirus that causes Acquired Immunodeficiency Syndrome (AIDS). This is a condition in humans that leads to ever-increasing immune system failure. Without treatment, the average survival time after infection is around 10 years. The human immunodeficiency virus is transferred via body fluids, and can only infect humans. It infects the immune system by targeting CD4+ helper T cells. As the infection progresses, apoptosis of CD4+ T cells decline their numbers to a critical level, leaving the body increasingly susceptible to opportunistic infections.

https://www.aids.gov/hiv-aids-basics/hiv-aids-101/statistics/

Today, the CDC reports that more than 1.2 million people in the United States currently live with an HIV infection, with nearly 1 in 7 unaware of their infection. There are currently 31 antiretroviral drugs (ARVs) with FDA approval to treat the HIV infection. However, none of these treatments cure or prevent HIV or Aids.

A recent study published in Nature examines the challenges of developing a HIV vaccine. One of the largest obstacles is the identification of mechanisms of protective immunity. Roederer et al., 2014 created a comparable model with simian immunodeficiency virus (SIV) in Indian origin rhesus macaques.

SIV is nonpathogenic in their natural hosts, however when an Asian or Indian rhesus macaque is exposed, the animal will develop simian AIDS (SAIDS). Virus strains from primate species are believed to have crossed the species barrier into humans, resulting in HIV-1 and HIV-2. The similarities between HIV and SIV make trials with the rhesus macaque ideal for vaccination studies in an organism comparable to humans.

Previous studies have given promising indications that among the five current human efficacy trials of HIV-1 vaccines, one has shown moderate success. The RV144 trial has been the most promising, however its efficacy has only been reported to be around 31%. Another trial, HVTN505, was predicted to be very effective in protecting against HIV, was halted for futility with no observed vaccine efficacy.  

http://phil.cdc.gov/phil/details.as 

In an attempt to study why these different human trials have not been successful, Roederer et al. examined SIV. This study utilizes a nonhuman primate model with a high amount of acquisition endpoints that are similar to human efficacy studies of HIV. This primate model was able to test and confirm that an envelope-elicited immune response to the virus is necessary and sufficient to protect against acquisition of the infection. In this study, SIV environment T cell mosaic immunogen (comparable to human helper T cells ) elicited more effective general responses, but less effective antibody responses. This study also was able to sequence and identify a sequence signature in the SIV envelope, which is possibly shared by HIV in humans, which can program the neutralization phenotype of viruses, affecting the entire surface of the protein.

This study examined three different vaccine groups of Indian rhesus monkey, and concluded that there was no association between protection from infection and protection from pathogenesis. This suggests that when developing in humans, responses that block initial infection are not the same cellular responses that will control the pathogenesis of an already present HIV infection.

The analysis of the effectiveness of SIV, and its comparability to HIV, enabled the study to provide insight into possible failures of the human HVTN505 and why RV1444 has had only moderate success. Similar vaccinations developed specifically for SIV envelope-expression vectors protected against a subset of neutralization sensitive viral variants, but did not generate an effective antibody response against specific variants. They are able to conclude that HVTN505 failed due to its inability to elicit antisera that completely neutralized circulating HIV-1 strains that are primarily neutralization resistant.

In contrast, RV144 has had moderate success, indicating that antibodies were successfully elicited and could neutralize some viruses circulating in the cohort, but not the more resistant varieties of the virus. 

http://upload.wikimedia.org/wikipedia/commons/7/7f/Rhesus_Macaques_-_cropped.jpg

Immune correlate studies that interrogate both virus sequences and immune responses can provide key insights on mechanisms of protection from HIV-1 acquisition. This study presented valuable insight into the similarities in the SIV and HIV strains, as well as reasoning behind the failure of various human efficacy trials of HIV vaccines.  

Ref:

1) Roederer M, Keele BF, Schmidt SD, Mason RD, Welles HC, Fischer W, et al. Immunological and Virological mechanisms of vaccine-mediated protection against SIV and HIV. Nature. 2014; 505:502-508.

2) Center for Disease Control and Prevention http://www.cdc.gov/hiv/default.html/

2) Sharp P, and Hahn B. Origins of HIV and the AIDS Pandemic. Cold Spring Harbor Perspectives in Medicine 2011; 1.1.

4) AIDS. gov https://www.aids.gov/