As mentioned in a recent post, a scientific workshop was held in July of this year to discuss research into HIV exposed but seronegative (HESN) individuals. The event was sponsored by the National Institute of Allergy & Infectious Diseases (NIAID) and followed up on a November 2009 conference on the same topic held in Manitoba, Canada. A report from the workshop is now available free online from AIDS Research & Human Retroviruses. Several presentations are summarized, including one by Bruce Walker relating to a study that is also now online in the new issue of the Journal of Infectious Diseases (abstracts and links to both articles are below).
Walker’s results caused some controversy in the field when they were first presented, because they failed to confirm prior reports of HIV-specific CD8 T cell responses in persistently seronegative partners of HIV-positive individuals. The study was rigorously designed with blinded analysis of immune responses, suggesting that some of the previous results may have been spurious. However, other explanations are possible, including differences in the intensity of exposure to HIV and the reported tendency of HIV-specific T cell responses to be only intermittently detectable in exposed uninfected individuals. Prior blinded studies in a cohort of sex workers in Nairobi--who may be more frequently exposed than partners in discordant couples--have detected HIV-specific CD8 T cell responses, but only in a subset of participants.
In another workshop talk, Andrew McMichael from Oxford reported detection of HIV-specific CD4 (but not CD8) T cell responses in the CHAVI002 cohort, which comprises both homosexual and heterosexual discordant couples. The report does not specify whether these analyses were blinded. McMichael’s group is now investigating whether HIV-specific T cell responses can be detected in stored samples from the placebo arm of the AIDSVAX vaccine trial.
Workshop participants identified several key questions that need to be answered to move the field forward:
- What mucosal parameters are distinctly different in the resistant population compared with exposed and infected populations?
- What is the nature of the host’s immune response at the first encounter with the virus if there is no pre-existing immunity?
- What host features (proteins/expression patterns/genes) or viral features are responsible for resistance?
A second International Symposium on Natural Immunity to HIV (ISNIH) is now being planned by investigators at the Public Health Agency of Canada in partnership with the University of Manitoba, and is expected to take place in June 2011.
AIDS Research and Human Retroviruses. -Not available-, ahead of print. doi:10.1089/AID.2010.0313.
Online Ahead of Editing: December 8, 2010
Janet M Young, Jim Turpin, Runa Musib, Opendra K Sharma.
The fascinating conundrum that some individuals who are exposed to HIV in ways that would make viral transmission highly likely, yet are able to remain uninfected has been appreciated for many years. As early as the late 1980’s, reports of such individuals began appearing in the HIV/AIDS literature. Despite the critical importance of understanding possible mechanisms of natural HIV resistance for developing effective prevention strategies, numerous obstacles have prevented this essential area of scientific exploration from moving forward. The Workshop held on July 8-9, 2010 and supported by OAR, NIAID, and NIDA at the NIH hosted 200 participants and utilized the expertise of 42 AIDS researchers as invited speakers, session chairs, and discussion leaders for presentations and breakout sessions in an attempt to remove some of those obstacles. Accomplishments of the participants included developing consensus for a new general term for the field, HESN or HIV Exposed Seronegative, while recognizing the necessity to identify and utilize secondary descriptive criteria such as exposure level, risk group, duration of seronegativity or natural resistance. Three key questions for future research were also identified by the group: (1) what it is different in HESN versus those who get infected?; (2) what is the immune response in HESN and is it just a marker of exposure or a correlate of protection?; and (3) what are the HESN host factors that help HESN resist infection? This report briefly summarizes the presentations, and describes future directions for addressing these questions and challenges.
Journal of Infectious Diseases Volume 203, Issue 2 Pp. 258-262
Marylyn M. Addo1,7, Marcus Altfeld1, Diana M. Brainard1,a, Almas Rathod1, Alicja Piechocka-Trocha1, Ulgen Fideli6,a, Joseph Mulenga6,a, Erin Shutes6,a, Donna Marie L. Alvino1, Eric Hunter2,3,4, Susan A. Allen2,3,6 and Bruce D. Walker1,5
1 Ragon Institute of MGH, MIT and Harvard, Charlestown, Massachusetts
2 Department of Pathology and Laboratory Medicine
3 Department of Global Health, Rollins School of Public Health
4 Department of Emory Vaccine Center at Yerkes, National Primate Research Center, Emory University, Atlanta, Georgia
5 Department of Howard Hughes Medical Institute, Chevy Chase, Maryland
6 Department of Rwanda Zambia HIV Research Group; Zambia Emory HIV Research Project, Lusaka, Zambia
7 Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachuetts
Reprints or correspondence: Dr Marylyn M. Addo, Ragon Institute of MGH, Harvard and MIT, 149 13th St, 6th Flr, Ste 6620, Charlestown, MA 02129-2000.
Human immunodeficiency virus type 1 (HIV-1)–specific T cell responses were characterized in a blinded study involving infected individuals and their seronegative exposed uninfected (EU) partners from Lusaka, Zambia. HIV-1–specific T cell responses were detected ex vivo in all infected individuals and amplified, on average, 27-fold following in vitro expansion. In contrast, no HIV-1–specific T cell responses were detected in any of the EU partners ex vivo or following in vitro expansion. These data demonstrate that the detection of HIV-1–specific T cell immunity in EU individuals is not universal and that alternative mechanisms may account for protection in these individuals.
Potential conflicts of interest: none reported.
Financial support: US National Institutes of Health (grants RO1 HD 40125, RO1 MH 66767, RO1 AI23980, RO1 AI40951, and RO1 AI51231), the Fogarty AIDS International Training and Research Program (FIC 2D43 TW001042), and Emory Center for AIDS Research (P30 AI050409).
Presented in part: The XIV International AIDS Conference, Barcelona, Spain, 2002 (abstract no. ThPeA7110).
a Present affiliation: Gilead Sciences Inc., Foster City, California (D.M.B.); United States Public Health Service, Walter Reed Army Medical Center (U.F.); Zambia National Blood Transfusion Service, Lusaka, Zambia (J.M.); and Bill and Melinda Gates Foundation (E.S.), Seattle, Washington.