Review Article | Published:

Unravelling the mechanisms of durable control of HIV-1

Nature Reviews Immunology volume 13, pages 487498 (2013) | Download Citation


Untreated HIV-1 infection typically progresses to AIDS within 10 years, but less than 1% of infected individuals remain healthy and have normal CD4+ T cell counts and undetectable viral loads; some individuals have remained this way for 35 years and counting. Through a combination of large population studies of cohorts of these 'HIV-1 controllers' and detailed studies of individual patients, a heterogeneous picture has emerged regarding the basis for this remarkable resistance to AIDS progression. In this Review, we highlight the host genetic factors, the viral genetic factors and the immunological factors that are associated with the controller phenotype, we discuss emerging methodological approaches that could facilitate a better understanding of spontaneous HIV-1 immune control in the future, and we delineate implications for a 'functional cure' of HIV-1 infection.

Key points

  • HIV controllers are a small group of HIV-1-infected patients who maintain undetectable or minimal levels of HIV-1 replication in the absence of antiretroviral therapy.

  • Many elite controllers harbour replication-competent viruses, and several studies have consistently failed to identify specific viral sequence abnormalities in these patients, which suggests that the controller phenotype is primarily achieved by host factors.

  • Genome-wide association studies have shown that genetic variations associated with HIV-1 immune control are exclusively located in the human HLA class I locus. Such genetic variations are most frequently detectable in the HLA-B binding pocket, but can also be found in selected areas encoding non-pocket elements of HLA-B or HLA-C.

  • Highly-potent HIV-1-specific CD8+ T cells seem to be the backbone of antiviral immune defence in many — but not all — elite controllers. These cells are highly effective at restricting HIV-1 replication in in vitro inhibition assays and they have functional and phenotypic characteristics that distinguish them from HIV-1-specific T cells from individuals with progressive HIV-1 infection.

  • Innate immune defence mechanisms are likely to modulate immune activity in HIV-1 controllers. In particular, dendritic cells, γδ T cells and the cell-intrinsic restriction of viral replication seem to support antiviral immune activities in HIV-1 controllers.

  • Elite controllers provide living evidence that the human immune system is able to effectively control HIV-1 replication. A better understanding of the mechanisms involved in HIV-1 immune control in these patients might enable the design of clinical strategies to improve the immune response to HIV-1 in broader patient populations.

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B.D.W. and X.G.Y. are supported by: the US National Institutes of Health grants AI098484, AI078799 and AI089339 (to X.G.Y.) as well as AI30914 and AI67073 (to B.D.W.); the Bill and Melinda Gates Foundation; the Mark and Lisa Schwartz Foundation; and the Phillip T. and Susan M. Ragon Foundation.

Author information


  1. Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Cambridge, Massachusetts 02139, USA.

    • Bruce D. Walker
    •  & Xu G. Yu
  2. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.

    • Bruce D. Walker


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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Bruce D. Walker.


CD4+ T cell counts

A normal CD4+ T cell count is 1,000 cells per microlitre (μl) of plasma, with a range of 600 to 1,400 cells per μl. The count falls during primary infection with HIV-1, then returns nearly to, or to lower than, normal levels. It then slowly falls, taking many years to reach the level of 200 cells per μl that characterizes the development of AIDS.

HIV-1 controllers

HIV-1-infected patients who spontaneously maintain very low levels of viral replication in the absence of antiretroviral therapy.

Elite controllers

HIV-1-infected patients who have undetectable levels of viral replication in the absence of antiretroviral therapy.

Genome-wide association studies

(GWASs). Studies that assess upwards of one million single-nucleotide polymorphisms in the human genome for associations with disease outcomes. As such, they require very large numbers of individuals; the number of individuals that are required depends on the strength of the associations that are being investigated.

Central memory T cells

Memory T cells that express L-selectin and CC-chemokine receptor 7 (CCR7) and that have the capacity to traffic from the blood to the secondary lymphoid organs. They have a nonpolarized differentiation state: they secrete interleukin-2 but not interferon-γ or interleukin-4. However, upon restimulation, they rapidly differentiate into cytokine-producing effector cells.

Highly active antiretroviral therapy

(HAART). An aggressive combination therapy against HIV-1 infection that typically includes three or more protease and reverse- transcriptase inhibitors.

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