Elsevier

Journal of Infection

Volume 48, Issue 1, January 2004, Pages 1-12
Journal of Infection

Review
AIDS in Africa: the impact of coinfections on the pathogenesis of HIV-1 infection

https://doi.org/10.1016/j.jinf.2003.09.001Get rights and content

Abstract

The intimate relationship between the HIV-1 life-cycle and the activation state of cells supporting viral replication results in a dynamic interaction between coinfections and HIV-1 replication in dually infected people. The immunologic impact of recurrent coinfections has the potential to increase viral replication, viral genotypic heterogeneity and CD4 T lymphocyte loss, leading to accelerated decline in immune function, reduced survival and increased HIV-1 transmission risk. These effects may play a particularly significant role in the HIV-1 epidemic in sub-Saharan Africa. The mechanisms underlying these effects on virus–host dynamics are reviewed and data describing the impact of tuberculosis, malaria, schistosomiasis and genital ulceration on HIV-1 infection are presented.

Introduction

The HIV-1 epidemic is having a devastating impact in sub-Saharan Africa. In 2002, it was estimated that 29.4 million people in the continent were living with HIV-1 infection and that the epidemic had claimed the lives of approximately 2.4 million Africans during that year.1 Indeed, HIV/AIDS accounts for, approximately 20% of deaths and disability-adjusted life-years lost in Africa.2 This epidemic in this region has developed on the background of a high pre-existing burden of infectious diseases, leading to potentially important disease interactions.

The natural history of HIV-1 infection is very variable; some individuals live with HIV-1 infection for over 10 years without developing significant immunosuppression, whereas, others may develop AIDS and die within one or two years. The rate of progression may be affected by many factors, relating to the infecting viral strain, host susceptibility and immune function as well as to exogenous influences such as access to healthcare and coinfections.3., 4., 5., 6. The relative importance of these factors may vary between populations in different regions of the world. This review addresses the hypothesis that frequent coinfections in HIV-1-infected individuals living in sub-Saharan Africa accelerate the progression of HIV-1 infection to AIDS, reduce survival and increase the risk of HIV-1 transmission.7., 8. In this region, the high prevalence of chronic and recurrent acute infections and relative inaccessibility to treatment for these conditions, may heighten any cofactor effect.

This review arises from the Barnett Christie Lecture delivered to the 9th Conference of the Federation of Infection Societies in November 2002. The mechanisms underlying the impact of coinfections on HIV-1 pathogenesis are reviewed and the findings of the author's own research in this field are presented.

Section snippets

Immune activation and HIV-1 replication

The HIV-1 life-cycle is intimately related to the level of activation of immune cells supporting viral replication. An increase in cellular activation in response to coinfections or immunisations may enhance viral replication by facilitating three key stages of the viral life-cycle; viral cellular entry, reverse transcription and proviral transcription.3

Viral cellular entry. HIV-1 particles typically gain entry to host cells by binding to the cell surface CD4 receptor and a chemokine

Tuberculosis and HIV-1 pathogenesis

Mycobacterium tuberculosis is a key opportunistic infection in HIV-1-infected individuals living in sub-Saharan Africa. In view of its high incidence, chronic course and associated systemic immune activation and proinflammatory cytokine drive,29., 30. TB is potentially an important cofactor in HIV-1 pathogenesis. Numerous in vitro studies have demonstrated the ability of M. tuberculosis to induce HIV-1 transcription in infected peripheral blood mononuclear cells.31., 32. In vivo, development of

Parasitic infections and HIV-1 pathogenesis

The huge burden of disease associated with parasitic infections in sub-Saharan Africa57 overlaps with the HIV-1 epidemic in this region. Despite the importance of determining the impact of these coinfections on HIV-1 pathogenesis, few studies address this issue as yet.

Coinfections and sexual transmission of HIV-1

There is a strong positive correlation between plasma HIV-1 load and risk of heterosexual HIV-1 transmission.69 Therefore, coinfections that lead to increased plasma viral load may potentially promote transmission. However, sexually transmitted infections within the genital tract itself clearly play a pivotal role in the heterosexual HIV-1 epidemic in sub-Saharan Africa.70., 71. The association with genital ulcer disease is particularly strong and it has been hypothesised that these

Epidemiological data on rate of progression to AIDS in Africa

Compelling in vitro and in vivo data have characterised the significant impact of immune activation associated with coinfections on HIV-1 replication and virus–host dynamics.3 Furthermore, high viral load is strongly associated with faster progression to AIDS.77 In view of these data, it is hypothesised that a high prevalence of coinfections leads to accelerated decline in immune function and shortened survival in HIV-1-infected individuals living in sub-Saharan Africa. To date, the rate of

Conclusions

The intimate relationship between the HIV-1 life-cycle and the activation state of the cells supporting viral replication results in a dynamic interaction between coinfections and HIV-1 pathogenesis. Systemic effects of recurrent coinfections potentially increase viral load, viral heterogeneity and CD4 cell loss leading to accelerated decline in immune function and reduced survival. These effects may be particularly important among those living in sub-Saharan Africa, although this remains

Acknowledgments

The Barnett Christie Lecture that forms the basis for this review was sponsored by the British Infection Society at the 9th Annual Conference at the Federation of Infection Societies. The author's work at the Centers for Disease Control and Prevention (CDC), Atlanta, USA was initially funded by a fellowship from the Wellcome Trust, London, UK (1997–1999) and then by a fellowship administered by the Oak Ridge Institute for Science and Education, Oak Ridge TN, USA (1999–2001). The author is

References (87)

  • M.S Cohen et al.

    Reduction of concentration of HIV-1 in semen after treatment of urethritis: implications for prevention of sexual transmission of HIV-1

    Lancet

    (1997)
  • D Morgan et al.

    HIV-1 disease progression and AIDS-defining disorders in rural Uganda

    Lancet

    (1997)
  • S.Z Wiktor et al.

    Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Cote d'Ivoire: a randomised controlled trial

    Lancet

    (1999)
  • UNAIDS/WHO. AIDS epidemic update. December 2002 www.unaids.org/worldaidsday/2002/press/Epiupdate.html Accessed June 12,...
  • Health Systems: Improving Performance

    (2000)
  • S.D Lawn et al.

    Contribution of immune activation to the pathogenesis and transmission of human immunodeficiency virus type 1 infection

    Clin Microbiol Rev

    (2001)
  • Y Huang et al.

    The role of a mutant CCR5 allele in HIV1 transmission and disease progression

    Nat Med

    (1996)
  • F Kirchoff et al.

    Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection

    N Engl J Med

    (1995)
  • T Harrer et al.

    Strong cytotoxic T cell and weak neutralizing antibody responses in a subset of persons with stable nonprogressing HIV type 1 infection

    AIDS Res Hum Retroviruses

    (1996)
  • S.M Wahl et al.

    Mycobacterium avium complex augments macrophage HIV-1 production and increases CCR5 expression

    Proc Natl Acad Sci USA

    (1998)
  • N.P Juffermans et al.

    Patients with active tuberculosis have increased expression of HIV coreceptors CXCR4 and CCR5 on CD4(+) T cells

    Clin Infect Dis

    (2001)
  • R Gaynor

    Cellular transcription factors involved in the regulation of HIV-1 gene expression

    AIDS

    (1992)
  • S.E Tong-Starksen et al.

    Differences in transcriptional enhancers of HIV-1 and HIV-2. Response to T cell activation signals

    J Immunol

    (1990)
  • K.M De Cock et al.

    Epidemiology and transmission of HIV-2. Why there is no HIV-2 pandemic

    JAMA

    (1993)
  • M.A Montano et al.

    Divergent transcriptional regulation among expanding human immunodeficiency virus type 1 subtypes

    J Virol

    (1997)
  • H.E Gendelman et al.

    Trans-activation of the human immunodeficiency virus long terminal repeat sequence by DNA viruses

    Proc Natl Acad Sci USA

    (1986)
  • E Maggi et al.

    Ability of HIV to promote a Th1 to Th0 shift and to replicate preferentially in Th2 and Th0 cells

    Science

    (1994)
  • C Graziosi et al.

    Lack of evidence for the dichotomy of Th1 and Th2 predominance in HIV-infected individuals

    Science

    (1994)
  • L Meyaard et al.

    Programmed death of T cells in HIV-1 infection

    Science

    (1992)
  • G Mancino et al.

    Infection of human monocytes with Mycobacterium tuberculosis enhances human immunodeficiency virus type 1 replication and transmission to T cells

    J Infect Dis

    (1997)
  • D.L Mann et al.

    HIV-1 transmission and function of virus-infected monocytes/macrophages

    J Immunol

    (1990)
  • Y Tsunetsugu-Yokota et al.

    Monocyte-derived cultured dendritic cells are susceptible to human immunodeficiency virus infection and transmit virus to resting T cells in the process of nominal antigen presentation

    J Virol

    (1995)
  • H Soudeyns et al.

    Selective pressure exerted by immunodominant HIV-1-specific cytotoxic T lymphocyte responses during primary infection drives genetic variation restricted to the cognate epitope

    Eur J Immunol

    (1999)
  • M.A Ostrowski et al.

    Expression of chemokine receptors CXCR4 and CCR5 in HIV-1-infected and uninfected individuals

    J Immunol

    (1998)
  • K.R Collins et al.

    Human immunodeficiency virus type 1 (HIV-1) quasispecies at the sites of Mycobacterium tuberculosis infection contribute to systemic HIV-1 heterogeneity

    J Virol

    (2002)
  • S.D Lawn et al.

    Tuberculosis and HIV infection are independently associated with elevated serum concentrations of tumour necrosis factor receptor type 1 and β2-microglobulin, respectively

    Clin Exp Immunol

    (2000)
  • G Vanham et al.

    Generalised immune activation in pulmonary tuberculosis: coactivation with HIV infection

    Clin Exp Immunol

    (1996)
  • M.M Lederman et al.

    Mycobacterium tuberculosis and its purified protein derivative activate expression of human immunodeficiency virus

    J Acquir Immune Defic Syndr

    (1991)
  • R.J Shattock et al.

    Phagocytosis of Mycobacterium tuberculosis modulates human immunodeficiency virus replication in human moncytic cells

    Res Virol

    (1994)
  • D Goletti et al.

    Effect of Mycobacterium tuberculosis on HIV replication. Role of immune activation

    J Immunol

    (1996)
  • Z Toossi et al.

    Impact of tuberculosis (TB) on HIV-1 activity in dually infected patients

    Clin Exp Immunol

    (2001)
  • C Whalen et al.

    Accelerated course of HIV infection after tuberculosis

    Am J Respir Care Med

    (1995)
  • C.C Whalen et al.

    Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda

    AIDS

    (2000)
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