Several years ago, Bruce Walker and colleagues from Partners AIDS Research in Boston launched the largest ever effort to research immunological control of HIV infection, the international HIV controllers study. The project is now proceeding under the aegis of the new Ragon Institute of Massachusetts General Hospital, created recently thanks to the generous support of the Ragon family. The HIV controllers study is collecting blood samples from both elite controllers, defined based on having a viral load less than 50 copies in the absence of any treatment, and viremic controllers, defined based on a viral load of between 50 and 2000 copies in the absence of treatment. A number of papers have been published already describing results from the study, and the latest has just appeared online in the Journal of Infectious Diseases.
The purpose of this investigation was to quantify the level of viral load among elite controllers using an ultra-sensitive assay that can measure down to a single copy of HIV RNA per ml. Among 90 individuals studied, the median viral load level was just 2 copies/mL. A longitudinal analysis of a subset of 31 participants demonstrated that 2-5-fold fluctuations in viral load were common. In terms of the relationship with immune responses, the researchers document a significant correlation between the breadth and potency of neutralizing antibody responses against HIV and the level of viral load detected. The breadth and magnitude of HIV-specific CD8 T cell responses, as measured solely by interferon-gamma production, did not show a correlation with viral load at these low levels.
An analysis of the relationship between viral load and the slope of CD4 decline was also conducted. The median time for which multiple CD4 measurements were available was 3.6 years (range 1 – 17.3), and the median number of measurements per person was seven. Although immune activation has previously been associated with CD4 T cell declines in elite controllers, in this analysis the median value of the slope per year was +11 cells/mm3.
Due the limited duration of follow up and number of measurements, the researchers note that in many cases the values were not significantly different from zero, indicating CD4 T cell counts were essentially stable over time. To try and get a better sense of which participants might be experiencing significant changes in CD4 counts, the researchers subsequently focused on individuals whose slopes were statistically different from zero. These analyses revealed that 5 out of 27 individuals (19%) with viral load levels less than 1 copy/mL experienced significant CD4 T cell count increases over time. The same was true for only 3 out of 50 individuals (3%) with HIV viral loads greater than 1 copy/mL. Conversely, 8 individuals experienced significant CD4 T cell declines, and all showed viral load levels over 1 copy/mL. An overall examination of the link between viral load level and CD4 T cell count slope showed a weak but significant correlation, with higher viral loads associated with CD4 T cell decline (r=-0.23; p=0.04).
Overall, the results suggest that the use of a viral load assay that is 250-fold more sensitive than those currently commercial available can reveal important information regarding elite control of HIV.
The Journal of Infectious Diseases 2009;200:000–000
DOI: 10.1086/605446
MAJOR ARTICLE
Persistent Low‐Level Viremia in HIV‐1 Elite Controllers and Relationship to Immunologic Parameters
Florencia Pereyra,1,2 Sarah Palmer,3,7 Toshiyuki Miura,1,6 Brian L. Block,1 Ann Wiegand,3 Alissa C. Rothchild,1 Brett Baker,1 Rachel Rosenberg,1 Emily Cutrell,1 Michael S. Seaman,4 John M. Coffin,5 and Bruce D. Walker1,6
1The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, 2Brigham and Women’s Hospital, Division of Infectious Diseases, 4Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, and 5Department of Molecular Biology and Microbiology, Tufts University, Boston Massachusetts; 3HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Frederick, and 6Howard Hughes Medical Institute, Chevy Chase, Maryland; and 7Virology Department, Swedish Institute for Infectious Disease Control and Karolinska Institute, Solna, Sweden
Background. Human immunodeficiency virus type 1 (HIV‐1) elite controllers are able to control virus replication to levels below the limits of detection by commercial assays, but the actual level of viremia in these individuals is not well defined. Here, we quantify plasma HIV‐1 RNA in elite controllers and correlate this with specific immunologic parameters.
Methods. Plasma HIV‐1 RNA levels were quantified in 90 elite controllers with use of a real time reverse‐transcriptase polymerase chain reaction assay with a sensitivity of 0.2 copies/mL. HIV‐1–specific immune responses and longitudinal CD4+ T cell counts were examined.
Results. The median plasma HIV‐1 RNA level was 2 copies/mL (interquartile range, 0.2–14 copies/mL). A longitudinal analysis of 31 elite controllers demonstrated 2–5–fold fluctuations in viremia in the majority of individuals; 6 had persistent levels below 1 copy/mL. Viremia correlated directly with HIV‐1–specific neutralizing antibodies and Western blot reactivity but not with CD8+ T cell responses. Absolute CD4+ T cell decrease was more common among individuals with detectable viremia (p=.04).
Conclusions. Low‐level viremia is present in the majority of elite controllers and is associated with higher HIV‐1–specific antibody responses. Absolute CD4+ T cell loss is more common among viremic individuals, suggesting that even very low‐level viremia has negative consequences over time.
Received 29 January 2009; accepted 21 April 2009; electronically published 4 August 2009.
Reprints or correspondence: Florencia Pereyra, MD, Ragon Institute, Massachusetts General Hospital, 149 13th St, Charlestown, MA 02129
Potential conflicts of interest: none reported
Presented in part: 15th Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, February 2008 (abstract 349).
Financial support: National Institutes of Health (AI28568 and AI30914 to B.D.W.), the Bill and Melinda Gates Foundation, the International AIDS Vaccine Initiative, and the Mark and Lisa Schwartz Foundation.
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