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Immune activation and the pathogenesis of HIV disease: implications for therapy.


Currently available data suggest that HIV infection causes disease in two phases (Figure 1). The first phase occurs during primary HIV infection and the early part of chronic infection when there is substantial depletion of memory (CCR5+) CD4+ T cells and disruption of the structure and function of secondary lymphoid tissues, especially the gut-associated lymphoid tissue (GALT) of the intestinal tract [1-4]. These early HIV-induced immune defects set the stage for the second phase of HIV disease, which is characterised by a state of persistent immune activation. Although suppression of HIV replication by antiretroviral therapy (ART) reduces immune activation, abnormalities may persist and contribute to residual immune dysfunction and non-AIDS HIV disease. It is therefore important to understand the mechanisms of the immune activation and devise therapeutic strategies to reverse it.



Several lines of evidence indicate that immune activation is the major cause of immune dysfunction in patients with chronic HIV infection (Table 1). The immune activation is reflected in an increased frequency of T cells expressing activatory and pro-apoptotic molecules such as HLA-DR, CD38 and Fas [5,6]. Lymphocytes and monocytes from HIV-infected individuals also display increased production of pro-inflammatory cytokines such as interleukin (IL)-1[beta] IL-6, IL-18 and tumour necrosis factor (TNF)-[alpha] [7]. In addition, there may be increased serum levels of proteins produced by immune cells, such as immunoglobulin A (IgA), neopterin and soluble cytotoxic T lymphocyte antigen 4 (sCTLA-4) [8]. This state of chronic immune activation is associated with a sustained rise in turnover (proliferation and death rates) of both CD4+ and CD8+ T cells [9,10], which in turn further enhances viral replication. Consequently, T cell activation and turnover correlate well with disease progression [11,12] and the rate of CD4+ T cell loss [13-15].

A rapid decrease in the expression of T cell activation markers (in parallel to the control of viral replication) is seen on initiation of ART [5,6,16-19]. Reductions in Fas/FasL expression [19,20], rates of T cell turnover [9,10] and levels of plasma pro-inflammatory cytokines [21] and plasma-soluble Fas [22] are observed. However, expression of activation markers may remain elevated compared to nonHIV-infected controls, even after long-term treatment [6,17,23,24]. This is particularly so for serum immune activation markers. For example, analyses undertaken

in patients who had received ART for 6 years with suppression of plasma HIV-RNA levels to <50 copies/ml demonstrated that serum levels of several immune activation markers were persistently increased [8].

ART-mediated decreases in the activation and turnover of CD4+ T cells are positively associated with the recovery of CD4+ T cells [6,25,26]. Poor recovery of CD4+ T cells in HIV patients on ART correlates with elevated expression of CD38, HLA-DR, Ki67 and CD57 on T cells [6,17,26,27] and increased rates of CD4+ T cell turnover [25]. An inverse relationship between CD8+ T cell activation and the recovery of CD4+ T cells is well established although reports on whether it predominantly influences early or late CD4+ T cell gains vary to some degree [17,28]. We and others have also demonstrated an inverse relationship between proportions of activated CD4+ T cells in the circulation and CD4+ T cell recovery in patients who achieve a virological response to ART [17,27]. Mechanisms linking persistent immune activation with poor CD4+ T cell recovery may include increased susceptibility of T cells to apoptosis [29,30], increased turnover of T cells leading to the accumulation of senescent T cells [25,27,31] and impaired T cell homeostasis resulting from reduced expression of CD127 (a component of the IL-7 receptor) [32].

Immune activation associated with chronic HIV infection is also associated with collagen deposition and fibrosis in supporting lymphoid tissues [4,33]. Increased expression of pro-inflammatory cytokines in lymph nodes can change the expression of cell surface adhesion molecules and mediate sequestration of T cells in lymph nodes, and alter cell-trafficking [34,35]. This potentially affects the survival of T cells, limits the ability of lymph nodes to support healthy T cell homeostasis and has been associated with reductions in the size of total and naive CD4+ T cell populations [4,33].


As well as depleting lymphocytes, HIV-associated immune activation may also increase the proportion of T cells that could adversely affect pathogen-specific T cell responses, such as senescent T cells and CD4+ regulatory T (Treg) cells. Treg cells are capable of suppressing T cell activation and proliferation and much research has addressed the role of these cells in disease pathogenesis [36-38]. During untreated HIV infection, Treg cell numbers are depleted in parallel with total CD4+ T cells [39-41]. Although loss of Treg cells has been suggested as a mechanism for increased immune activation in HIV disease, we and others have demonstrated that the frequency of circulating CD4+ T cells with a regulatory phenotype (FoxP3+CD25+ or FoxP3+CD127LO) is elevated in untreated HIV-infected patients compared with uninfected controls [39,42-46], and correlates directly with plasma HIV-RNA level as well as the frequency of activated CD4+ T cells [39,43,44,46]. Furthermore, in untreated HIV disease, patients with low CD4+ T cell counts exhibit higher frequencies of CD4+ Treg cells compared with patients who have higher CD4+ T cell counts [41,44].

There is debate, however, as to whether FoxP3+CD25+ or FoxP3+[CD127.sup.LO] CD4+ T cells in HIV-infected patients are bona fide Treg cells or activated non-regulatory CD4+ T cells. Upregulation of FoxP3 and CD25 without conferment of suppressive function has been demonstrated in CD4+ T cells following cellular activation [47,48], while reduced expression of CD127 is a feature of activated CD4+ T cells in patients with progressive HIV disease [32]. Recent studies by our group and others have shown that a large proportion of FoxP3-expressing CD4+ T cells also co-express markers of immune activation (HLA-DR, CD38, Ki-67, PD-1), and that these cells are most common in patients with untreated disease [42,43,49]. Thus, expression of FoxP3 in T cells of HIV-infected patients may not necessarily discriminate activated bona fide Treg cells from recently activated cells that do not possess suppressive activity [43,50].


The causes of immune activation in chronic HIV infection have not been fully elucidated but recent work has focused upon two potential mechanisms. Following studies that demonstrated the rapid and sustained depletion of CD4+ T cells from mucosal tissues during acute HIV infection [1,3,4], Brenchley et al. hypothesised that the profound loss of CD4+ T cells leads to a breakdown of the gut mucosal barrier and subsequent translocation of microbial products from the intestinal lumen into the circulation where the activation of immune cells may occur [51]. Subsequent studies have demonstrated elevation of bacterial lipopolysaccharide (LPS) and 16S ribosomal DNA levels in the plasma of both untreated and treated HIV-infected subjects as well as associations between these indicators of microbial translocation and levels of immune activation [52,53]. Furthermore, indicators of microbial translocation correlate with blunted CD4+ T cell gains in HIV-infected subjects receiving ART [52]. Together, these data support a role for immune activation induced by microbial translocation as a cause of the CD4+ T cell depletion that characterises HIV disease.

A recent study in a murine model of polyinosinic:polycytidylic acid (poly I:C)-induced thymic ablation suggests that translocation of gut microbial products might be particularly detrimental to naive CD4+ T cell homeostasis [54]. This was not mirrored in the naive CD8+ T cell population. Furthermore, transfer of naive CD4+ and CD8+ T cells into poly I:C-treated mice demonstrated rapid proliferation and acquisition of activation markers among naive CD4+ T cells but not naive CD8+ T cells, suggesting that naive CD4+ T cells alone react to a changed environment in poly I:C-treated mice. Interestingly, our own studies of immune activation in HIV patients receiving ART suggest that the relationship between increased immune activation and poor recovery of naive CD4+ T cell numbers is most clearly evident in patients lacking a thymus [27].

The downstream sequelae of the interaction between HIV gp120 and the CD4 molecule may also be an important mechanism underlying HIV-associated immune activation. This interaction triggers production of IFN-[alpha] by plasmacytoid dendritic cells (pDC), which increases production of soluble TRAIL as well as upregulation of membrane-bound TRAIL (mTRAIL) and induction of DR5 (a TRAIL receptor) expression on CD4+ T cells. As mTRAIL and DR5 are both expressed on CD4+ T cells but not CD8+ T cells, this model may explain the preferential depletion of CD4+ T cells in HIV infection [55-58]. Further evidence of a role for pDC and IFN-[alpha] in the immune activation of HIV infection has been provided from studies of SIV infection [59] and the observation that interferon-stimulated gene transcripts are markedly upregulated in activated CD4+ T cells from untreated HIV-infected subjects [60].


Persistent immune activation in patients with HIV infection that is 'optimally' suppressed by ART may not only contribute to residual immune dysfunction but also to abnormally high levels of inflammation. This has the potential to be a factor in the pathogenesis of atherosclerotic vascular disease [61] and possibly type 2 diabetes, osteoporosis and dementia, particularly in HIV patients who are ageing. Several therapeutic approaches to suppressing immune activation are currently under consideration. Patients who apparently have optimal control of HIV replication may continue to experience viral replication that is only detectable by assaying plasma samples using methods that detect HIV-RNA levels much

lower than 50 copies/ml [62]. One approach to controlling residual immune activation is therefore to 'intensify' ART by adding another drug from a different class, such as an HIV integrase inhibitor. In ACTG study A5244, raltegravir was added to the current ART regimen in patients with a plasma RNA level <50 copies/ml after >12 months of treatment. Preliminary results indicate that HIV-RNA levels did not change but that there was an increase in CD4+ T cell counts [63].

In patients with evidence of increased translocation of microbial products from the intestine into the circulation, decreasing intestinal bacterial load might reduce immune activation. One approach to achieving this is to administer oral bovine colostrum, which contains antibodies that are effective in the gastrointestinal tract. The BITE study evaluated bovine colostrum in combination with other agents that together improve immune function in the gut. Of the 340 ART-naive patients enrolled, participants in the active arm had a significantly slower decline in CD4+ T cell counts compared with patients in the control arm over 1 year [64]. The CORAL study is an ongoing study in Australia in which both hyperimmune colostrum obtained from cattle vaccinated with gastrointestinal bacteria and 'intensification' of ART with raltegravir are being evaluated.

Finally, another approach to controlling persistent HIV-associated immune activation is to suppress pDC activation and production of IFN-[alpha] This approach is being taken in systemic lupus erythematosus (SLE), in which IFN-[alpha] is a mediator of immunopathology [65] and might contribute to the inflammation underlying the increased risk of atherosclerotic vascular disease in SLE patients [66].


Immune activation is central to the pathogenesis of immune dysfunction in patients with HIV infection. Although contemporary ART is effective for long periods of time, some patients in whom plasma HIV RNA cannot be detected may have persistent immune activation that adversely affects immune reconstitution and may be a risk factor for non-AIDS HIV disease. The causes of the immune activation have not been completely defined but probably include reservoirs of low-level HIV replication and absorption of microbial products from the intestine because of failure to reconstitute the mucosal immune system. Future treatment programmes for patients with HIV infection might include therapies that suppress immune activation but there is currently insufficient information to predict what these might be.


[1.] Brenchley JM, Schacker TW, Ruff LE et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med, 2004, 200, 749-759.

[2.] Levesque MC, Moody MA, Hwang KK et al. Polyclonal B cell differentiation and loss of gastrointestinal tract germinal centers in the earliest stages of HIV-1 infection. PLoS Med, 2009, 6, e1000107.

[3.] Mehandru S, Poles MA, Tenner-Racz K et al. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med, 2004, 200, 761-770.

[4.] Schacker TW, Nguyen PL, Beilman GJ et al. Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis. J Clin Invest, 2002, 110, 1133-1139.

[5.] Al-Harthi L, Voris J, Becker S et al. Evaluation of the impact of highly active antiretroviral therapy on immune recovery in antiretroviral naive patients. HIV Med, 2004, 5, 55-65.

[6.] Benito JM, Lopez M, Lozano S et al. Differential upregulation of CD38 on different T-cell subsets may influence the ability to reconstitute CD4+ T cells under successful highly active antiretroviral therapy. J Acquir Immune Defic Syndr, 2005, 38, 373-381.

[7.] Connolly NC, Riddler SA, Rinaldo CR. Proinflammatory cytokines in HIV disease: a review and rationale for new therapeutic approaches. AIDS Rev, 2005, 7, 168-180.

[8.] French MA, King MS, Tschampa JM et al. Serum immune activation markers are persistently increased in patients with HIV infection after 6 years of antiretroviral therapy despite suppression of viral replication and reconstitution of CD4(+) T cells. J Infect Dis, 2009, 200, 1212-1215.

[9.] Hazenberg MD, Cohen Stuart JWT, Otto SA et al. T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). Blood, 2000, 95, 255.

[10.] Mohri H, Perelson AS, Tung K et al. Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy. J Exp Med, 2001, 194, 1277-1287.

[11.] Giorgi JV, Hultin LE,McKeating JA et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis, 1999, 179, 859-870.

[12.] Simmonds P, Beatson D, Cuthbert RJ et al. Determinants of HIV disease progression: six-year longitudinal study in the Edinburgh haemophilia/HIV cohort. Lancet, 1991, 338, 1159-1163.

[13.] Bofill M, Mocroft A, Lipman M et al. Increased numbers of primed activated CD8+CD38+CD45RO+ T cells predict the decline of CD4+ T cells in HIV-1-infected patients. AIDS, 1996, 10, 827-834.

[14.] Deeks SG, Kitchen CM, Liu L et al. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood, 2004, 104, 942-947.

[15.] Rodriguez B, Sethi AK, Cheruvu VK et al. Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. J Am Med Assoc, 2006, 296, 1498-1506.

[16.] Autran B, Carcelain G, Li TS et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science, 1997, 277, 112-116.

[17.] Hunt PW, Martin JN, Sinclair E et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis, 2003, 187, 1534-1543.

[18.] Landay A, Bettendorf D, Chan E et al. Evidence of immune reconstitution in antiretroviral drug-experienced patients with advanced HIV disease. AIDS Res Hum Retroviruses, 2002, 18, 95-102.

[19.] Lederman MM, Connick E, Landay A et al. Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine and ritonavir: results of AIDS Clinical Trials Group Protocol 315. J Infect Dis, 1998, 178, 70-79.

[20.] Sloand EM, Kumar PN, Kim S et al. Human immunodeficiency virus type 1 protease inhibitor modulates activation of peripheral blood CD4(+) T cells and decreases their susceptibility to apoptosis in vitro and in vivo. Blood, 1999, 94, 1021-1027.

[21.] Aiuti F, Mezzaroma I. Failure to reconstitute CD4+ T-cells despite suppression of HIV replication under HAART. AIDS Rev, 2006, 8, 88-97.

[22.] De Milito A, Hejdeman B, Albert J et al. High plasma levels of soluble fas in HIV type 1-infected subjects are not normalized during highly active antiretroviral therapy. AIDS Res Hum Retroviruses, 2000, 16, 1379-1384.

[23.] Almeida CA, Price P, French MA. Immune activation in patients infected with HIV type 1 and maintaining suppression of viral replication by highly active antiretroviral therapy. AIDS Res Hum Retroviruses, 2002, 18, 1351-1355.

[24.] Valdez H, Connick E, Smith KY et al. Limited immune restoration after 3 years' suppression of HIV-1 replication in patients with moderately advanced disease. AIDS, 2002, 16, 1859-1866.

[25.] Anthony KB, Yoder C, Metcalf JA et al. Incomplete CD4 T cell recovery in HIV-1 infection after 12 months of highly active antiretroviral therapy is associated with ongoing increased CD4 T cell activation and turnover. J Acquir Immune Defic Syndr, 2003, 33, 125-133.

[26.] Mildvan D, Bosch RJ, Kim RS et al. Immunophenotypic markers and antiretroviral therapy (IMART): T cell activation and maturation help predict treatment response. J Infect Dis, 2004, 189, 1811-1820.

[27.] Fernandez S, Price P, McKinnon EJ et al. Low CD4+ T-cell counts in HIV patients receiving effective antiretroviral therapy are associated with CD4+ T-cell activation and senescence but not with lower effector memory T-cell function. Clin Immunol, 2006, 120, 163-170.

[28.] Benito JM, Lopez M, Lozano S et al. CD4+ T cell recovery beyond the first year of complete suppression of viral replication during highly active antiretroviral therapy is not influenced by CD8+ T-cell activation. J Infect Dis, 2005, 192, 2142-2146.

[29.] Benveniste O, Flahault A, Rollot F et al. Mechanisms involved in the low-level regeneration of CD4+ cells in HIV-1 infected patients receiving highly active antiretroviral therapy who have prolonged undetectable plasma viral loads. J Infect Dis, 2005, 191, 1670-1679.

[30.] Hansjee N, Kaufmann GR, Strub C et al. Persistent apoptosis in HIV-1-infected individuals receiving potent antiretroviral therapy is associated with poor recovery of CD4 T lymphocytes. J Acquir Immune Defic Syndr, 2004, 36, 671-677.

[31.] Papagno L, Spina CA, Marchant A et al. Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection. PLOS Biol, 2004, 2, 0173-0185.

[32.] Sasson SC, Zaunders JJ, Zanetti G et al. Increased plasma interleukin-7 level correlates with decreased CD127 and Increased CD132 extracellular expression on T cell subsets in patients with HIV-1 infection. J Infect Dis, 2006, 193, 505-514.

[33.] Schacker TW, Brenchley JM, Beilman GJ et al. Lymphatic tissue fibrosis is associated with reduced numbers of naive CD4+ T cells in human immunodeficiency virus type 1 infection. Clin Vaccine Immunol, 2006, 13, 556-560.

[34.] Andersson J, Fehniger TE, Patterson J et al. Early reduction of immune activation in lymphoid tissue following highly active HIV therapy. AIDS, 1998, 12, 123-129.

[35.] Bucy RP, Hockett RD, Derdeyn CA et al. Initial increase in blood CD4+ lymphocytes after HIV antiretroviral therapy reflects redistribution from lymphoid tissues. J Clin Invest, 1999, 103, 1391-1398.

[36.] Boasso A, Vaccari M, Nilsson J et al. Do regulatory T-cells play a role in AIDS pathogenesis? AIDS Rev, 2006, 8, 141-147.

[37.] Seddiki N, Kelleher AD. Regulatory T cells in HIV infection: who's suppressing what? Curr HIV/AIDS Rep, 2008, 5, 20-26.

[38.] Sempere JM, Soriano V, Benito JM. T regulatory cells and HIV infection. AIDS Rev, 2007, 9, 54-60.

[39.] Cao W, Jamieson BD, Hultin LE et al. Regulatory T cell expansion and immune activation during untreated HIV type 1 infection are associated with disease progression. AIDS Res Hum Retroviruses, 2009, 25, 183-191.

[40.] Eggena MP, Barugahare B, Jones N et al. Depletion of regulatory T cells in HIV infection is associated with immune activation. J Immunol, 2005, 174, 4407-4414.

[41.] Montes M, Lewis DE, Sanchez C et al. Foxp3+ regulatory T cells in antiretroviral-naive HIV patients. AIDS, 2006, 20, 1669-1671.

[42.] Bi X, Suzuki Y, Gatanaga H, Oka S. High frequency and proliferation of CD4+ FOXP3+ Treg in HIV-1-infected patients with low CD4 counts. Eur J Immunol, 2009, 39, 301-309.

[43.] Lim A, French MA, Price P. CD4+ and CD8+ T cells expressing FoxP3 in HIV-infected patients are phenotypically distinct and influenced by disease severity and antiretroviral therapy. J Acquir Immune Defic Syndr, 2009, 51, 248-257.

[44.] Lim A, Tan D, Price P et al. Proportions of circulating T cells with a regulatory cell phenotype increase with HIV-associated immune activation and remain high on antiretroviral therapy. AIDS, 2007, 21, 1525-1534.

[45.] Ndhlovu LC, Loo CP, Spotts G et al. FOXP3 expressing CD127lo CD4+ T cells inversely correlate with CD38+ CD8+ T cell activation levels in primary HIV-1 infection. J Leukoc Biol, 2008, 83, 254-262.

[46.] Rallon NI, Lopez M, Soriano V et al. Level, phenotype and activation status of CD4+FoxP3+ regulatory T cells in patients chronically infected with human immunodeficiency virus and/or hepatitis C virus. Clin Exp Immunol, 2009, 155, 35-43.

[47.] Allan SE, Crome SQ, Crellin NK et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol, 2007, 19, 345-354.

[48.] Pillai V, Ortega SB,Wang CK, Karandikar NJ. Transient regulatory T-cells: a state attained by all activated human T-cells. Clin Immunol, 2007, 123, 18-29.

[49.] Card CM, McLaren PJ,Wachihi C et al. Decreased immune activation in resistance to HIV-1 infection is associated with an elevated frequency of CD4(+)CD25(+)FOXP3(+) regulatory T cells. J Infect Dis, 2009, 199, 1318-1322.

[50.] Wang R, Kozhaya L, Mercer F et al. Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. Proc Natl Acad Sci USA, 2009, 106, 13439-13444.

[51.] Brenchley JM, Price DA, Douek DC. HIV disease: fallout from a mucosal catastrophe. Nat Immunol, 2006, 7, 235-239.

[52.] Jiang W, Lederman MM, Hunt P et al. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis, 2009, 199, 1177-1185.

[53.] Brenchley JM, Price DA, Schacker TW et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med, 2007, 12, 1365-1371.

[54.] Bourgeois C, Hao Z, Rajewsky K et al. Ablation of thymic export causes accelerated decay of naive CD4 T cells in the periphery because of activation by environmental antigen. Proc Natl Acad Sci USA, 2008, 105, 8691-8696.

[55.] Herbeuval JP, Boasso A, Grivel JC et al. TNF-related apoptosis-inducing ligand (TRAIL) in HIV-1-infected patients and its in vitro production by antigen presenting cells. Blood, 2005, 105, 2458-2464.

[56.] Herbeuval JP, Grivel JC, Boasso A et al. CD4+ T-cell death induced by infectious and noninfectious HIV-1: role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis. Blood, 2005, 106, 3524-3531.

[57.] Herbeuval JP, Hardy AW, Boasso A et al. 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 USA, 2005, 102, 13974-13979.

[58.] Herbeuval JP, Shearer GM. HIV-1 immunopathogenesis: how good interferon turns bad. Clin Immunol, 2007, 123, 121-128.

[59.] Mandl JN, Barry AP, Vanderford TH et al. Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med, 2008, 14, 1077-1087.

[60.] Sedaghat AR, German J, Teslovich TM et al. Chronic CD4+ T-cell activation and depletion in human immunodeficiency virus type 1 infection: type I interferon-mediated disruption of T-cell dynamics. J Virol, 2008, 82, 1870-1883.

[61.] Baker JV, Duprez D, Rapkin J et al. Untreated HIV infection and large and small artery elasticity. J Acquir Immune Defic Syndr, 2009, 52, 25-31.

[62.] Palmer S, Maldarelli F, Wiegand A et al. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci USA, 2008, 105, 3879-3884.

[63.] Gandhi R, Zheng S, Bosch R et al. Raltegravir (RAL) intensification does not reduce low-level residual viremia in HIV-1-infected patients on antiretroviral therapy (ART): results from ACTG A5244. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009. Abstract WELBB1.

[64.] Lange J, Gazzard B, Diaz R et al. Reduced CD4+ T cell decline and immune activation by NR100157, a specific multi-targeted nutritional intervention, in HIV-1 positive adults not on antiretroviral therapy (BITE). 48th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, USA, September 2009. Abstract H-1230b.

[65.] Ronnblom L, Pascual V. The innate immune system in SLE: type I interferons and dendritic cells. Lupus, 2008, 17, 394-399.

[66.] Haque S, Mirjafari H, Bruce IN. Atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus. Curr Opin Lipidol, 2008, 19, 338-343.

[67.] Chun TW, Carruth L, Finzi D et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature, 1997, 387, 183-188.

[68.] Douek DC, Brenchley JM, Betts MR et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature, 2002, 417, 95-98.

[69.] Finkel TH, Tudor-Williams G, Banda NK et al. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med, 1995, 1, 129-134.

[70.] D'Orsogna LJ, Krueger RG, McKinnon EJ, French MA. Circulating memory B-cell subpopulations are affected differently by HIV infection and antiretroviral therapy. AIDS, 2007, 21, 1747-1752.

[71.] Fauci AS, Mavilio D, Kottilil S. NK cells in HIV infection: paradigm for protection or targets for ambush. Nat Rev Immunol, 2005, 5, 835-843.

[72.] Roederer M, Dubs JG, Anderson MT et al. CD8 naive T cell counts decrease progressively in HIV-infected adults. J Clin Invest, 1995, 95, 2061-2066.

[73.] Chakrabarti LA, Lewin SR, Zhang L et al. Normal T-cell turnover in sooty mangabeys harboring active simian immunodeficiency virus infection. J Virol, 2000, 74, 1209-1223.

[74.] Michel P, Balde AT, Roussilhon C et al. Reduced immune activation and T cell apoptosis in human immunodeficiency virus type 2 compared with type 1: correlation of T cell apoptosis with beta2 microglobulin concentration and disease evolution. J Infect Dis, 2000, 181, 64-75.

[75.] Baenziger S, Heikenwalder M, Johansen P et al. Triggering TLR7 in mice induces immune activation and lymphoid system disruption, resembling HIV-mediated pathology. Blood, 2009, 113, 377-388.

Correspondence to: Martyn French, Department of Clinical Immunology, Royal Perth Hospital, GPO Box X2213, Perth WA 6847, Australia Email:


(1) School of Pathology and Laboratory Medicine, University of Western Australia and (2) Department of Clinical Immunology, Royal Perth Hospital and Path West Laboratory Medicine, Perth, Australia
Table 1. Evidence that HIV-induced immune activation is a major
cause of immune dysfunction in chronic HIV infection

The frequency of CD4+ T cells infected by HIV in vivo       [67,68]
is too low to account for the CD4 T cell loss

Most apoptotic CD4+ T cells in peripheral blood and         [69]
lymph nodes of patients with chronic HIV infection are
not infected by HIV
Naive CD8+ T cells, memory B cells and NK cells as          [70-72]
well as CD4+ T cells decline in HIV infection

SIV-infected macaques exhibit a persistently activated      [73]
immune system and rapidly progress to AIDS, while
SIV-infected sooty mangabeys show normal T cell
division rates and do not progress to AIDS

HIV-2 infection is associated with lower levels of          [74]
immune activation, which may explain the slower decline
of CD4+ T cells compared with HIV-1 infection

In mice, TLR7 stimulation unrelated to a virus infection    [75]
induces immune activation and immunopathology similar
to that in HIV infection
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Title Annotation:LEADING ARTICLE
Author:Fernandez, Sonia; Lim, Andrew; French, Martyn
Publication:Journal of HIV Therapy
Article Type:Report
Geographic Code:8AUST
Date:Nov 1, 2009
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