AIDS in Africa

We would like to add a layer of complexity to, and maybe shed some light on, interactions between AIDS and other infectious diseases recently summarised by Corbett and colleagues (June 22, p 2177).1 Immunological results collected over time in the Gulu district of north Uganda, where prevalence of HIV infection ranges between 14% and 25%, show that lymphocytes from African HIV-infected individuals are abnormally activated. Thus, production of interferon γ and interleukin 10 by HIV-antigen-stimulated peripheral blood mononuclear cells of African HIV-infected individuals is higher than in European patients. Immune activation in the African setting is not limited to HIV-infected individuals: production of interferon γ and interleukin 10 is greatly augmented in HIV-uninfected individuals as well. This abnormal activation is associated with environmental conditions, including parasitic infections, poor hygienic conditions, and dietary limitations, since the immune response resumes a Th1-dominant pattern in Africans who move to Western countries.2 Susceptibility to HIV infection is thought to be higher, and disease progression faster, in African individuals than in European individuals. How could the peculiar cytokine profile seen in the African setting affect susceptibility to infection and the rate of progression to AIDS? In vitro, interferon γ and interleukin 10 increase expression of chemokine receptor 5 (CCR5)—one of the main coreceptors for HIV on the surface of immune cells. Data show that CCR5 is indeed upregulated in vivo in African individuals.2 The potential importance of this observation is underlined by results indicating that HIV infection in Africa is mostly supported by R5 viruses—ie the viral strain that uses CCR5 as its coreceptor.3 Thus, immune activation would provoke upregulation of CCR5 on target cells, and this would result in an evolutionary pressure on the viral quasispecies, leading to the preferential selection of R5 HIV strains. The net result is prevalence of R5 virus within a biological scenario (upregulation of CCR5) that facilitates infection of target cells. Because CCR5-expressing cells are concentrated in the female genital tract,4 and HIV infection in Africa is mainly heterosexually transmitted, the immune scenario detected in Africa could also be at least partly responsible for a facilitated heterosexual transmission of HIV infection. This hypothesis is strengthened by preliminary data gathered in the Marashtra-mumbai region of India. In fact, despite the observation that R5 viruses are prevalent in this region,5 cells of HIV-infected and HIV-uninfected Marashtra-mumbai individuals mostly express the chemokine receptor CXCR4 (unpublished data). CXCR4 upregulation is seen in the presence of an immune profile that overlaps the one seen in African individuals, but that is also distinguished by abnormally increased secretion of interleukin 4, the cytokine that induces CXCR4. In this scenario, characterised by the discordance between the predominant HIV strain and the prevalent viral coreceptor, progression of HIV infection is slower and similar to the one seen in Western countries.