Immune Activation Raised HIV Risk in CAPRISA Trial, but Some Develop Protective Antibodies

Women in the CAPRISA 004 vaginal gel trial who showed evidence of prior immune activation had an increased likelihood of becoming infected with HIV, researchers recently reported. Another CAPRISA analysis found that 2 women exhibitedbroadly cross-neutralizing antibodies targeting a newly emergent antigen on HIV's envelope -- a discovery that could advance vaccine research.

The CAPRISA 004 trial compared a 1% tenofovir vaginal gel versus placebo gel, administered before and after sex, in nearly 900 women at risk for HIV at 2 sites in KwaZulu-Natal, South Africa. At study entry the women (age 18 to 40 years) were HIV negative, not pregnant, and sexually active.

As first reported at the 2010 International AIDS Conference in Vienna, tenofovir gel reduced the risk of HIV acquisition by 39%. Several analyses have since looked at the study findings in more detail as researchers sought to learn what factors are associated with protection or infection.

As described in the October 1, 2012, Journal of Infectious Diseases, Vivek Naranbhai, Salim and Quarraisha Abdool Karim, and fellow CAPRISA 004 investigators looked at what role pre-existing immune activation might play in HIV acquisition, hoping to identify potential strategies to increase the effectiveness of tenofovir gel.

The researchers measured levels of more than a dozen cytokines and cellular immune mediators including platelets and natural killer cells in a subset of 44 women randomly assigned to the tenofovir gel or placebo gel arms who became HIV infected during follow-up, as well as 37 women who reported the highest amount of sexual exposure but did not become infected.

Regardless of tenofovir gel use, women who acquired HIV had significantly greater systemic innate immune activation prior to infection than those who remained HIV negative. Higher levels of pro-inflammatory and T-cell regulating cytokines (e.g., tumor necrosis factor alpha, interleukin 2, interleukin 7), as well as higher platelet counts and larger number of activated natural killer cells, were associated with greater risk of HIV infection, both alone and in combination.

Non-specific immune activation makes target cells more easily infected by HIV and may impair specific immune responses against the virus, Salim Abdool Karim explained.

Hence, the investigators suggested, "an innate immune activation suppressant could be added to tenofovir gel as a potential combination gel strategy in developing the next generation of higher efficacy antiretroviral microbicides."

Potential Vaccine Advance

The second study, described in the October 21, 2012, advance online edition of Nature Medicine, shed further light on how a small proportion of people with HIV naturally develop broadly cross-neutralizing antibodies after many years of infection.

CAPRISA researchers performed a follow-up study of 2 women -- 1 from CAPRISA 004 and 1 from the CAPRISA 002 acute infection study -- who had antibodies targeting a specific glycan (sugar molecule) on HIV's gp120 envelope protein. This glycan, known as Asn332, was not present on the HIV strains that initially infected the women, but emerged within 6 months due to immune pressure from weaker antibodies.

"These findings highlight the dynamic interplay between early antibodies and viral escape in driving the evolution of conserved broadly cross-neutralizing antibody epitopes," the researchers wrote.

Below is an edited excerpt from a press release issued by the University of the Witswatersrand in Johannesburg describing the study findings in more detail.

New Study Discovers Unique HIV Feature

24 October 2012 -- Two Wits researchers led an AIDS study published today in the journal, Nature Medicine, which describes how a unique change in the outer covering of the virus found in two HIV infected South African women enabled them to make potent antibodies which are able to kill up to 88% of HIV types from around the world.

This ground-breaking discovery provides an important new approach that could be useful in making an AIDS vaccine.

The study, performed by members of the Centre for the Aids Programme of Research in South Africa (CAPRISA) consortium, involves scientists from Wits University, the National Institute for Communicable Diseases (NICD) in Johannesburg, the University of KwaZulu-Natal, and the University of Cape Town, who have been studying, over the last 5 years, how certain HIV-infected people develop very powerful antibody responses. 

These antibodies are referred to as broadly neutralizing antibodies because they kill a wide range of HIV types from different parts of the world. This CAPRISA team initially discovered that 2 KwaZulu-Natal women, 1 of whom participated in the CAPRISA 004 tenofovir gel study, could make these rare antibodies.

Through long-term follow-up laboratory studies on these 2 women, the team led by Wits researchers and Centre for HIV and STI at the National Institute for Communicable Diseases of the National Health Laboratory Service based scientists Dr. Penny Moore and Professor Lynn Morris, discovered that a sugar (known as a glycan) on the surface protein coat of the virus at a specific position (referred to as position 332) forms a site of vulnerability in the virus and enables the body to mount a broadly neutralizing antibody response.

"Understanding this elaborate game of 'cat and mouse' between HIV and the immune response of the infected person has provided valuable insights into how broadly neutralizing antibodies arise," said Moore. 

Morris, Head of AIDS Research at the NICD explained: “We were surprised to find that the virus that caused infection in many cases did not have this antibody target on its outer covering. But over time, the virus was pressured by body’s immune reaction to cover itself with the sugar that formed a point of vulnerability, and so allowed the development of antibodies that hit that weak spot."

"Broadly neutralizing antibodies are considered to be the key to making an AIDS vaccine. This discovery provides new clues on how vaccines could be designed to elicit broadly neutralizing antibodies. The world needs an effective AIDS vaccine to overcome the global scourge of AIDS," said Professor Salim Abdool Karim, Director of CAPRISA and President of the Medical Research Council, in his comments on the significance of the finding.

While their existence has been known for a while, highly potent forms of broadly neutralizing antibodies against HIV were only identified about 3 years ago. Until now, it was not known how the human body is able to make broadly neutralizing antibodies.

This study discovered 1 mechanism by which these antibodies may be made. To make this discovery, the research team studied the target of some of these antibodies, a sugar that coats the surface protein of HIV, forming a site of vulnerability. By tracing back the evolution of the virus that elicited these antibodies, this team showed that this particular weak point was absent from the virus that first infected these women. 

However, under constant pressure from other less powerful antibodies that develop in all infected people, their HIV was forced to expose this vulnerability over time. This allowed the broadly neutralizing antibodies to develop. 

Analysis of a large number of other viruses from throughout the world, performed in collaboration with scientists from the University of North Carolina and Harvard University, suggest that the vulnerability at position 332 may be present at the time of infection in about two-thirds of subtype C viruses (the subtype most common in Africa). Hence, if a vaccine is developed to target this glycan only, it may not be able to uniformly neutralize all subtype C viruses; as a result AIDS vaccines may need to attack multiple targets on the virus.

11/6/12

References

V Naranbhai, SS Abdool Karim, M Altfeld, et al (CAPRISA 004 TRAPS team). Innate immune activation enhances HIV acquisition in women, diminishing the effectiveness of tenofovir microbicide gel. Journal of Infectious Diseases 206(7):993-1001. October 1, 2012.

PL Moore, ES Gray, CK Wibmer, L Morris, et al. Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape. Nature Medicine. October 21, 2012 (Epub ahead of print).

JPM Langedijk and H Schuitemaker. A sweet surprise for HIV broadly neutralizing antibodies. Nature Medicine. October 21, 2012 (Epub ahead of print).

Other Source

University of the Witwatersrand. New Study Discovers Unique HIV Feature. Press release. October 24, 2012