HIV infection: first battle decides the war

doi:10.1016/j.it.2006.04.007

Trends in Immunology

Volume 27, Issue 6, June 2006, Pages 274-281

https://doi.org/10.1016/j.it.2006.04.007 Get rights and content

The traditional view of HIV-1 infection characterized by the slow decline of CD4⁺ T cells has radically changed in light of recent observations in rhesus macaques and humans of rapid and extensive infection and removal of memory CD4⁺ T cells in mucosal tissues within the first three weeks of infection. This initial strike to the immune system seems to be the distinguishing feature of HIV-1 pathogenesis and its extent sets the overall course of the ensuing infection. Qualitatively different mechanisms of CD4⁺ T-cell depletion prevail during the acute, chronic and advanced phases of infection depending on the availability of the target-cell population and competence of the immune system. The elimination of CD4⁺ T cells in mucosal lymphoid tissues results in the absence of important regulatory and effector functions that these cells normally perform in controlling immune responses to environmental antigens and pathogens. Ablation of acute HIV-1 viremia limits the initial damage to the CD4⁺ T-cell compartment and helps to establish a state of equilibrium between the replicating virus, the availability of the target-cell population and the immune control characteristic of long-term non-progression.

Section snippets

The mystery of HIV pathogenesis

For years, researchers have wondered which singular feature enables HIV-1 to undermine the immune system continuously until it can no longer protect the host. Most nonlytic viruses infecting humans are rapidly cleared during the initial acute stage of infection or establish a long-term relationship with the host based on a mutual compromise often described as ‘infection–immunity’. In this state of controlled asymptomatic chronic infection, the virus acts as a responsible tenant avoiding

First hit: the initial depletion of memory CD4⁺ T cells

Irrefutable evidence now shows that HIV-1 and simian immunodeficiency (SIV) infections have a significantly greater initial impact on the mucosal immune system than on its systemic counterpart. The earliest and most profound alterations manifested by the marked loss of CD4⁺ T cells occur in mucosal tissues, particularly in the gut-associated lymphoid tissue (GALT), before analogous changes are detectable in the peripheral blood and lymph nodes. Marked abnormalities in the intestinal T-cell

IFN-α: guardian angel or little devil?

An alternative, intriguing scenario that could explain the rapid loss of CD4⁺ T cells has transpired from the observations recently published by the Shearer group 24, 25 (Figure 1e). Their findings indicate that IFN-α, usually thought of as a cytokine with powerful antiviral activity, can become a liability in HIV-1 infection where it might be responsible for CD4⁺ T-cell depletion. Plasmacytoid dendritic cells (pDCs) produce large quantities of type I interferons following stimulation with

The long term: post-acute events

It is well established that HIV-1 and SIV infections induce a state of intense immune activation associated with the extensive proliferation and turnover of T cells, including CCR5⁺ CD4⁺ memory T cells, which can serve as a target population for the virus [18]. Consistent with this, Li et al. [21] reported a switch from the wide-spread infection of resting CD4⁺ T cells, after this population has been almost eliminated in the acute phase, to the low-frequency infection of activated CD4⁺ T cells

Killing the defense: the depletion of HIV-1-specific CD4⁺ T cells

The initial destruction of memory CD4⁺ T cells seems to have special consequences for a concurrently recruited subpopulation of CD4⁺ T cells specific for HIV. The observation that these cells are preferentially targeted by HIV-1 [33] is unsurprising given their spatial and temporal co-localization with HIV-producing cells in the local microenvironment of infected lymphoid tissue and the state of activation induced by the recognition of cognate HIV-1 epitopes. HIV-specific CD4⁺ T cells and

The impact of CD4⁺ T-cell depletion on antibody responses

Numerous reports convincingly document the essential role of CD4⁺ T cells and their soluble products in the switching and differentiation of B lymphocytes into IgA-secreting cells 6, 44, 45, 46. Thus, T-cell-produced cytokines, such as IL-5, IL-6, IL-10, transforming growth factor (TGF)-β and others, regulate such processes, with some variances depending on the species (mice versus humans) and experimental conditions. Nevertheless, HIV-1-induced CD4⁺ T-cell depletion in mucosal tissues, and

Implications for vaccine development

Can the initial depletion of HIV-1-specific CD4⁺ T cells be partially evaded by their prior expansion through immunization? A general pessimism regarding the beneficial role of vaccine-induced virus-specific CD4⁺ T cells existed in the field, based on the argument that these cells might serve as additional sites for viral replication and further fuel the initial infection. However, this argument loses its appeal when considering the studies discussed previously that demonstrate the high

New take on an old story

The near-complete elimination of memory CD4⁺ T-cell populations in mucosal lymphoid tissues during the initial stage of HIV-1 infection abrogates the important regulatory and effector functions that these cells usually have in controlling immune responses to environmental antigens and commensal bacteria on the one hand and infecting pathogens on the other 69, 70. The removal of memory CD4⁺ T cells from mucosal tissues is compensated partially by the increased production and immigration of newly

Acknowledgements

We are supported in part by NIH grants R21-AI063967 and U19-AI28147.

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Trends in Immunology

HIV infection: first battle decides the war

Section snippets

The mystery of HIV pathogenesis

First hit: the initial depletion of memory CD4+ T cells

IFN-α: guardian angel or little devil?

The long term: post-acute events

Killing the defense: the depletion of HIV-1-specific CD4+ T cells

The impact of CD4+ T-cell depletion on antibody responses

Implications for vaccine development

New take on an old story

Acknowledgements

Curr. Opin. Immunol.

Gastroenterology

Blood

Trends Microbiol.

Blood

Blood

Immunity

Clin. Immunol.

Trends Immunol.

Vaccine

On natural and artificial vaccinations

Annu. Rev. Immunol.

The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus

Nature

Helping the CD8+ T-cell response

Nat. Rev. Immunol.

T cell dynamics in HIV-1 infection

Annu. Rev. Immunol.

Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues

Annu. Rev. Immunol.

Immunological study of the rectal mucosa of men with and without human immunodeficiency virus infection

Gut

Simian immunodeficiency virus infection of the gastrointestinal tract of rhesus macaques. Functional, pathological, and morphological changes

Am. J. Pathol.

Getting to the guts of HIV pathogenesis

J. Exp. Med.

Selective depletion of rectal lamina propria rather than lymphoid aggregate CD4 lymphocytes in HIV infection

Clin. Exp. Immunol.

Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection

Nature

Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract

J. Exp. Med.

Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection

Science

CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract

J. Exp. Med.

Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive simian immunodeficiency virus infection

J. Exp. Med.

Dynamics of CCR5 expression by CD4+ T cells in lymphoid tissues during simian immunodeficiency virus infection

J. Virol.

Vaginal CD4+ T cells express high levels of CCR5 and are rapidly depleted in simian immunodeficiency virus infection

J. Infect. Dis.

Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells

Nature

Functional expression of Fas and Fas ligand on human gut lamina propria T lymphocytes. A potential role for the acidic sphingomyelinase pathway in normal immunoregulation

J. Clin. Invest.

HIV-1 gp120 accelerates Fas-mediated activation-induced human lamina propria T cell apoptosis

J. Clin. Immunol.

Regulation of TNF-related apoptosis-inducing ligand on primary CD4+ T cells by HIV-1: role of type I IFN-producing plasmacytoid dendritic cells

Proc. Natl. Acad. Sci. U. S. A.

First hit: the initial depletion of memory CD4⁺ T cells

Killing the defense: the depletion of HIV-1-specific CD4⁺ T cells

The impact of CD4⁺ T-cell depletion on antibody responses

Helping the CD8⁺ T-cell response

Population biology of HIV-1 infection: viral and CD4⁺ T cell demographics and dynamics in lymphatic tissues

Massive infection and loss of memory CD4⁺ T cells in multiple tissues during acute SIV infection

Primary HIV-1 infection is associated with preferential depletion of CD4⁺ T lymphocytes from effector sites in the gastrointestinal tract

Gastrointestinal tract as a major site of CD4⁺ T cell depletion and viral replication in SIV infection

CD4⁺ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract

Insufficient production and tissue delivery of CD4⁺ memory T cells in rapidly progressive simian immunodeficiency virus infection

Dynamics of CCR5 expression by CD4⁺ T cells in lymphoid tissues during simian immunodeficiency virus infection

Vaginal CD4⁺ T cells express high levels of CCR5 and are rapidly depleted in simian immunodeficiency virus infection

Peak SIV replication in resting memory CD4⁺ T cells depletes gut lamina propria CD4⁺ T cells

Regulation of TNF-related apoptosis-inducing ligand on primary CD4⁺ T cells by HIV-1: role of type I IFN-producing plasmacytoid dendritic cells