INTRODUCTION — Although HIV-1 infection is associated with most of the global AIDS pandemic, HIV-2 is an important cause of infection and disease in certain regions of the world where it is endemic, most notably West Africa. People living with HIV-2 infection can be found in most countries and regions globally, so it is an important consideration in patients with an AIDS-like illness [1].
This topic will address the epidemiology, transmission, natural history, and pathogenesis of HIV-2 infection. The clinical manifestations, diagnosis, and treatment of HIV-2 are discussed elsewhere. (See "Clinical manifestations and diagnosis of HIV-2 infection" and "Treatment of HIV-2 infection".)
EPIDEMIOLOGY — As of the end of 2021, the Joint United Nations Programme on HIV and AIDS (UNAIDS) and the World Health Organization (WHO) estimate that approximately 38.4 million people are living with HIV/AIDS; by crude estimates, approximately one to two million of these people are living with HIV-2 [2-5], including some who are dually infected with both viruses [2-4,6-8].
Origin of the epidemic — Serologic evidence of a second human immunodeficiency virus was first discovered in 1985 in Senegal [9] with subsequent isolation of HIV-2 documented in 1986 from a Cape Verdean patient [10]. Similar to HIV-1, HIV-2 was initially a zoonosis, originally transmitted from West African Sooty mangabeys (Cercocebus atys) to humans [11-13]. Serologic data suggest that HIV-2 may have been circulating as early as 1966 [14] while phylogenetic evidence dates its introduction into humans during the first half of the 20th century [15,16]. (See "Global epidemiology of HIV infection", section on 'Origin of the HIV pandemic'.)
HIV-2 in West Africa — HIV-2 is endemic in West Africa, although data over the past decade suggest that epidemiologic trends may be shifting [17-19]. Several African countries (eg, Senegal, Gambia, Cote D’Ivoire, Guinea-Bissau) have reported declining prevalence rates of HIV-2 over time [17-22].
As an example, a cross-sectional survey performed from 1996 to 2006 among 3242 individuals living in Guinea-Bissau demonstrated that the incidence of HIV-2 was declining and was half that of HIV-1 infection, when compared with a similar serosurvey from 1987 to 1996 [19,23].
Additionally, the prevalence of HIV-2 decreased among persons below 45 years of age, but not among older individuals [19]. This observation may be due to a cohort effect, where previously infected individuals are aging with HIV-2 infection, which is less pathogenic than HIV-1 [19]. Other explanations include: a) lower rates of sexual transmission of HIV-2 compared with HIV-1 and b) screening of the blood supply for HIV-2, which was initiated in 1987. (See 'Transmission' below.)
HIV-2 outside West Africa — Regions and countries outside of West Africa reporting HIV-2 infections include: North America (United States, Canada), South America and Caribbean (Brazil, Columbia, Argentina, Venezuela, Cuba), Europe (France, Spain, Portugal, United Kingdom, Sweden, Germany, Italy, Switzerland, Netherlands, Belgium, Greece, Turkey, Russia), the Middle East (Lebanon, Israel, Egypt, Saudi Arabia), Asia-Oceania (India, Pakistan, Philippines, China, Nepal, Japan, South Korea, Australia, New Zealand), and southern, central, and northern Africa (Zimbabwe, Angola, Mozambique, South Africa, Gabon, Equatorial Guinea, Democratic Republic of the Congo, Morocco) [2,24].
In the United States, the first case of HIV-2 infection was reported in 1987 [25]. The total number of cases of HIV-2 in the United States is small, with only 166 cases reported to the United States Centers for Disease Control and Prevention (CDC) between 1987 and 2009 [26]. In updated surveillance data from 2010 to 2017, only 198 of 327,700 (0.06 percent) of new HIV diagnoses reported to the CDC were due to HIV-2; of these, patients were classified as having HIV-2 monoinfection (102), dual HIV-1 and HIV-2 infection (11), or probable but unconfirmed HIV-2 infection (85) [27]. Most experts suspect the number of HIV-2 infections is a likely underestimate; there have been 46 cases of HIV-2 diagnosed in New York City between 2010 and 2020 (three had dual HIV-1/HIV-2 infection); in addition, 25 had probable HIV-2 infection [28]. Many other urban areas (eg, Chicago, Boston, Washington, DC) also include immigrants from West Africa where HIV-2 is endemic [1,29]. The prevalence of HIV-2 may also be underestimated since most people living with HIV-2 are asymptomatic and may never have been tested for HIV infection.
Dual infection with HIV-1 and HIV-2 — Dual infection with HIV-1 and HIV-2 can occur in locales where both viruses cocirculate [6-8]. Dual infection has been reported most commonly in West Africa where it is estimated that approximately 5 to 10 percent of individuals with HIV are coinfected with HIV-2 [3,20,30-33].
Although one observational study in Senegalese female sex workers suggested that HIV-2 infection may be protective against HIV acquisition [34], these results were not corroborated by subsequent reports [35-37].
TRANSMISSION
Routes of transmission — HIV-1 and HIV-2 share similar routes of transmission including sexual contact, blood-borne exposure (eg, blood transfusions, shared needles) and perinatal transmission.
Screening of the blood supply has virtually eliminated transmissions via this route in developed countries [38]. The risk of HIV-2 infection has also declined in some African countries, such as Guinea-Bissau, Senegal, and Cote d'Ivoire, where HIV screening of the blood supply was initiated early in the HIV epidemic [23,39,40].
Risk of transmission — Transmission of HIV-2 appears to be less efficient than HIV-1 [41-47]. This is particularly notable when comparing perinatal transmission rates for these two viruses [48]. For example, in studies of pregnant women in The Gambia or the Ivory Coast, the relative risk of transmission was 6- to 21-fold lower among women with HIV-2 compared to those with HIV-1 [43,47].
The lower risk of transmission of HIV-2 may be related to lower levels of viremia that are seen among infected patients compared with those with HIV-1. Compared with HIV-1, lower levels of HIV-2 shedding have also been found in the genital tracts of men and women, which may also help to explain the lower rates of HIV-2 transmission through sexual contact [41,45,49]. (See 'Natural history' below.)
NATURAL HISTORY
HIV-2 is less pathogenic than HIV-1 — Multiple studies suggest that HIV-2 is generally less pathogenic than HIV-1. Chronic HIV-1 infection is characterized by rising levels of viremia and progressive immunologic decline in association with opportunistic infections that eventually lead to death in untreated persons. Compared with HIV-1, HIV-2 infection is characterized by [41-46,49-58]:
●A longer asymptomatic stage of infection
●Slower declines of CD4+ T cell counts
●Lower levels of plasma viremia in chronically infected patients
Risk of AIDS — The slower natural history of HIV-2 infection was well illustrated in an observational study in Senegal; 46 commercial sex workers with HIV-1 infection and 103 with HIV-2 infection were recruited and followed serially from 1985 to 1993 [51]. Over the course of the study, the probability of AIDS-free survival was higher among HIV-2 compared with HIV-1 infected women (100 percent versus 67 percent). In addition, a subset of women with incident HIV-1 seroconversion (n = 32) were significantly more likely to have a decline in CD4 cell counts (<400 cells/microL) than those with incident HIV-2 seroconversion (n = 33). In a natural history study comparing HIV-1 and HIV-2 in 872 patients from Guinea-Bissau, with 23 years of follow-up, the median time from HIV infection to development of AIDS was significantly longer in those with HIV-2 (14.3 versus 6.2 years) [58].
Risk of death — Persons with HIV-2 infection and a CD4 count >500 cells/microL appear to have a lower risk of dying compared to those with HIV-1 infection and a similar immune status [59]. However, mortality rates among patients with HIV-1 and HIV-2 infection with advanced disease appear similar when adjusting for CD4 cell count, age, and sex [57].
Several studies have evaluated the risk of death in persons living with HIV-2 [60-63]. A meta-analysis that included seven studies comparing HIV-1- versus HIV-2-monoinfected individuals reported a mortality rate ratio of 1.86 (95% CI 1.44-2.39) [62]. In a study from rural Guinea-Bissau, which included 285 patients with HIV-2 and 117 patients with HIV-1 with up to 19 years of follow-up, the median time to death for individuals with HIV-2 and HIV-1 was approximately 15 and 7 years, respectively [60]. Another study reported the probability of survival in 133 individuals with HIV-2 stratified by viral load [61]. Among the 85 patients with a detectable HIV-2 viral load (>100 copies/mL), the median time to death was about 7.5 years for those in the high viral load strata (>10,000 copies/mL) and about 11 years for those in the medium viral load strata (101 to 10,000 copies/mL). In the natural history study comparing HIV-1 and HIV-2 infection described above, the median survival time after HIV infection was significantly longer for those with HIV-2 (15.6 versus 8.2 years) [58].
Lower levels of viremia — When matched for disease stage, studies of persons living with HIV-2 infection demonstrate that plasma viremia is significantly lower compared to those with HIV-1 infection [64]. Low levels of viremia are also associated with slower declines of CD4 cell counts and lower rates of viral evolution among individual patients with HIV-2 infection compared with those with HIV-1 [65]. Lower levels of viremia are also seen among recent HIV-2 seroconverters; in one study, the viral load set point was approximately 28-fold lower after seroconversion among those with HIV-2 than with HIV-1 infection [66]. HIV-2-specific immune responses may help to control viremia in early stages of infection [66-69].
However, for each logarithmic increase in viral load in patients with HIV-2, the rate of CD4 T cell decline is similar to that seen in patients with HIV-1 [52]. Thus, the level of viremia may influence the development of advanced immunodeficiency [70].
Natural history among dually infected patients — The natural history of HIV-1 infection may be altered by coinfection with HIV-2 [60,62,66,71-78]. As an example, a cohort study found that the median time to AIDS was longer in 32 patients with dual infection compared with 119 patients with HIV-1 alone (104 versus 68 months) [77]. Extended follow-up of this cohort found that mortality in dually infected individuals was also lower [78]. However, a meta-analysis that included data from six studies found no difference in mortality between those with dual infection compared with HIV-1 monoinfection (mortality rate ratio 1.11, 95% CI 0.95-1.30) [62].
PATHOGENESIS — The mechanisms underlying the divergent natural history patterns between HIV-1 and HIV-2 infections are unclear.
In patients with HIV-1 infection, systemic immune activation is an independent marker of disease progression [79]. Immune activation may result from microbial translocation of bacterial cell wall products (eg, lipopolysaccharide), which occurs secondary to HIV-related invasion and disruption of the gastrointestinal mucosa [80,81]. Cross-sectional studies of patients with HIV in the United States have demonstrated that different stages of HIV disease are associated with higher levels of circulating lipopolysaccharide (LPS) and markers of monocyte activation (sCD14) and decreased endotoxin core antibody (EndoCAb) levels [79,82]. However, one longitudinal study in Africa did not support a role for microbial translocation among African patients with HIV-1 infection [83]. These opposing observations may be related to different modes of transmission or differences in baseline cytokine levels due to chronic intestinal infections, which could alter the immune response to HIV-1 infection.
There are few studies that have examined the role of microbial translocation or chronic immune activation and disease progression in persons with HIV-1 and HIV-2 infection [64,80,84-87]. These observational studies have demonstrated the following key findings:
●Some studies have suggested that patients with HIV-2 may have lower levels of immune activation compared with those with HIV-1, thus accounting for slower rates of disease progression [84], while others have found comparable levels among patients with similar stages of clinical disease [80].
●There are also conflicting data as to whether there is a direct relationship between viral load and markers of T cell activation [64,80,85-87].
●However, several studies do suggest that immune activation (as measured by the cellular expression of HLA-DR and CD38 on CD4+ and CD8+ T cells and T cell receptor excision DNA circle [TREC] levels) is directly associated with CD4+ T cell depletion in patients with HIV-2, as previously described in HIV-1 infection [64,80,84,86]. Another study that examined the role of microbial translocation found a direct correlation between increased LPS levels and loss of CD4 T cells in both those with HIV-1 and HIV-2 infection alike [85].
Emerging data from independent studies suggests that the HIV-2 capsid and its interaction with the host viral restriction factor TRIM5a may play a role in HIV-2's attenuated pathogenesis and reduced transmission compared to HIV-1 [88-90].
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Similar to HIV-1, HIV-2 was initially a zoonosis, originally transmitted from West African Sooty mangabeys to humans. (See 'Origin of the epidemic' above.)
HIV-2 is endemic in West Africa, but has also been reported in more than two dozen countries on every continent except Antarctica. Accurate estimates on the number of cases worldwide are lacking. (See 'HIV-2 outside West Africa' above.)
Dual infection with HIV-1 and HIV-2 can occur in locales where both viruses cocirculate. (See 'Dual infection with HIV-1 and HIV-2' above.)
●Transmission – HIV-1 and HIV-2 share similar routes of transmission including sexual contact, blood-borne exposure (eg, blood transfusions, shared needles) and perinatal transmission. (See 'Transmission' above.)
Transmission of HIV-2 appears to be less efficient than HIV-1. This observation may be related to the lower levels of plasma viremia and genital shedding that is observed among patients with HIV-2. (See 'Transmission' above.)
●Natural history – Multiple studies suggest that HIV-2 is generally less pathogenic than HIV-1. Compared with HIV-1, HIV-2 infection is characterized by a longer asymptomatic stage of infection, slower declines of CD4 cell counts and lower levels of plasma viremia. (See 'Natural history' above.)
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