Infection with HIV-2

Introduction and history In 1985, a group of healthy Senegalese whose sera demonstrated much stronger antibody responses to simian immunodeficiency virus (SIV) than to the HIV type 1 (HIV-1) was first described [1]. In 1986, this new retrovirus was isolated, which is now known as HIV type 2 (HIV-2) [2,3]. Although both HIV-1 and HIV-2 belong to the lentivirus subfamily, and their genomic organization is similar [4], HIV-2 is only about 40% similar to HIV-1 in nucleotide sequence and is more closely related to SIV, with approximately 75% (or greater, see later) nucleotide sequence similarity [4-6]. Although both HIV-1 and HIV-2 can cause acquired immune deficiency syndrome (AIDS), the clinical and biological characteristics of infection with these two viruses show substantial differences, as well as similarities [7]. In particular, HIV-2 is less readily transmitted and is generally less pathogenic than is HIV-1 [8,9]. In this paper, we review what is presently known about HIV-2. Epidemiology The Centers for Disease Control began tracking AIDS in the United States in 1981 [10] and began testing blood donations for the presence of HIV-2 in 1992, after retrospectively testing for the presence of HIV-2 in samples donated from 1987 to 1989 [11,12]. To date, 800 000 Americans have been infected with HIV, the vast majority of these being HIV-1 infections [10]. As of 31 January 2000, the Centers for Disease Control had identified 80 HIV-2-infected individuals in the United States [13]. Infection with HIV-2 was first described in urban settings in Africa [1] and appears to have been present in the area since at least 1966 [14,15]. The prevalence of HIV-2 remains highest in Western Africa and in countries that have socio-economic ties with the area [16]. Thus, moderate to high rates of infection have been found in urban areas of most West African countries, as well as in Angola and Mozambique, which are former Portuguese colonies (reviewed in [16-18]). Portugal, with several former colonies in Western Africa, has the highest incidence of HIV-2 in Europe, with HIV-2 being responsible for 4.5% of all AIDS cases [19]. In one study, greater than 60% of all newly diagnosed HIV-2 infections in Portugal could not be directly traced back to a West African contact, demonstrating its entrenchment in the local population [19]. Tracking the exact prevalence of HIV-2 in Africa remains difficult due to various factors, including a non-stationary population, and differing techniques in the collection and analysis of prevalence data. However, studies suggest that Guinea-Bissau has the highest prevalence of HIV-2 infection [16]. In 1987, in a random sampling of inhabitants of multi-family houses, infection rates for HIV-2 were 8.9% in those persons older than 15 years old and 20% in those older than 40 years old [20]. In Guinnea-Bissau, a prevalence of 13.4% in asymptomatic men has been reported [21]. Studies generally suggest a decreasing prevalence of HIV-2 infection in West Africa: from 1985 to 1996, nine out of 10 nations studied showed decreasing HIV-2 prevalence rates in blood donors (except Nigeria, reviewed in [22]), and from 1988 to 1992, in pregnant women in the Ivory Coast, the prevalence of HIV-2 dropped from 2.6 to 1.5% [23]. However, the decrease in HIV-2 prevalence coincides with an increasing prevalence of HIV-1 infection, which is spreading at a rate much faster than is the drop in HIV-2 prevalence [22,23]. Only very low rates of HIV-2 infection are found outside of West Africa, Portugal, or countries that were previously Portuguese colonies, such as Mozambique and Angola. Between June 1992 and June 1995, 62 people in the United States were reported to have HIV-2 infection. Only three of those were found among blood donors, out of 74 million donations [24]. Most of the HIV-2-infected individuals had clear links to western Africa, either through birth or sexual partners [24]. Seventy-five cases of HIV-2 infection had been reported in France by 1994, with 58 of those being among people who came directly from West Africa [16]. Evolution of HIV-2 Analyses of serological data indicate that HIV-2 and SIV are closely related [1]. All SIV proteins are immunoprecipitated by sera from HIV-2-positive patients [1]. Multiple independent zoonotic transmissions between the primate hosts of different groups of SIV and humans were thus suspected as the ultimate source of HIV-2 infection. Five lines of evidence are used to substantiate zoonotic transmission of SIV into humans: (i) overall similarities in viral genome organization, (ii) phylogenetic relatedness, (iii) geographic coincidence, (iv) prevalence in the natural host, and (v) plausible routes of transmission [25-28]. Thus, evidence that at least some subtypes of HIV-2 came from SIVsm, a lentivirus found in Sooty Mangabey monkeys (Cercocebus atys), comes from their highly similar genomic structure, including the presence of the accessory gene vpx (a gene unique to HIV-2 and SIV). Furthermore, Sooty Mangabeys, like HIV-2, are found in western Africa and have a high prevalence of natural infection with SIVsm, and these monkeys are commonly hunted for food, followed by exposure to potentially infected body fluids and tissues during butchering. Orphan monkeys are often kept as pets, and one study found that, between 1988 and 1989, two out of 25 pet Sooty Mangabeys from West Africa were found to be infected with SIVsm, demonstrating an additional potential route for transmission [29]. In addition, SIVsm and HIV-2 are phylogenetically related. In fact, SIVsm and HIV-2 isolated from the same area are more related to each other than to SIVsm from a different area, and cannot be separated into distinct phylogenetic lineages according to species of origin [30]. SIV and HIV-2 also share a large amount of nucleotide similarity (approximately 75%). In fact, the HIV-2 pol and env gene sequences cluster within SIV lineages, showing that HIV-2 in humans and SIV in mangabeys are members of a single diverse virus family [6,27,30,31]. HIV-2 appears to have emerged from at least seven different zoonotic transmissions of a primate lentivirus to humans, resulting in the seven known subtypes of HIV-2 (A-G) [27,32,33]. Although previously it was believed that HIV-1 and HIV-2 came from a single zoonotic crossover event [4,34], HIV-1 now appears to be a crossover from chimpanzee (Pan troglodytes troglodytes) lentiviruses, such as SIVcpz[26,27]. Although SIV appears to cause no disease in its natural host [31,35], in spite of an often high level of viral replication, introduction into an unnatural host primate (human or simian) can result in an acquired immunodeficiency syndrome [27,35]. Does HIV-2 protect against infection by HIV-1? Based on cohorts of Senegalese sex workers with a stable prevalence of HIV-2, Travers et al. found an HIV-1 incidence rate of 2.53 among uninfected control subjects, but only an incidence of 1.06 among HIV-2-positive subjects (an approximately 70% rate of protection), even though the incidence rate of gonorrhea (used as a marker of sexual activity and exposure to sexually transmitted diseases) was significantly higher among HIV-2-positive subjects [36]. Additional studies have found protection rates from 52 to 74%, depending on the study design [37,38], and lower HIV-1 viral loads have been seen in HIV-2/HIV-1 dually infected individuals than in patients with only HIV-1 infection [39]. These findings have been questioned, however, by other groups working in other parts of West Africa [37,38,40-43]. Any protective effect of HIV-1 on subsequent HIV-2 infection could not be readily evaluated [36,44]. While controversy continues as to the epidemiological evidence concerning a protective effect of HIV-2 against HIV-1 infection, several possible biological mechanisms for this potential protective effect have been explored. Arya and Gallo found that HIV-2 decreases HIV-1 replication at the molecular level. The inhibition appeared to be caused by a complex pathway [44]. The HIV-2 Tat activation response (TAR) RNA element has also been shown to inhibit HIV-1 transactivation and replication, presumably by competing for HIV-1 Tat or crucial cellular factors, thus inhibiting their interaction with HIV-1 TAR [45,46]. A robust cross-reactive immune response has also been implicated in this inhibition of HIV-1. A majority of HIV-2-positive individuals possess cytotoxic T lymphocyte responses able to recognize HIV-1 gag epitopes, and some individuals can recognize HIV-1 epitopes from multiple clades [47]. In another study, peripheral blood lymphocytes from HIV-2-positive Senegalese prostitutes with high-risk behavior were shown to be 50-fold more resistant than control peripheral blood lymphocyte cultures to HIV-1Bal (a macrophage-tropic, CCR5-using virus) challenge. However, resistance to HIV-1MN was less dramatic (10-fold) and not statistically significant [48]. In a similar study, one-half of HIV-2-infected commercial sex workers in Senegal had peripheral blood mononuclear cells (PBMC) capable of resisting infection by HIV-1JR-CSF (a macrophage-tropic, CCR5-using virus), while the same cells were readily susceptible to infection by HIV-1IIIB, a CXCR4-using virus [49]. In both studies, depletion of CD8-positive T cells or β-chemokines variably reduced the ability to resist HIV-1 viral challenge [48,49]. Broad virus-neutralizing activity in sera has been associated with long-term survival of SIV-infected monkeys, and with decreased maternal-child transmission in HIV-1 [50]. Such neutralizing activity is rare in HIV-1 infection, but is more common in HIV-2 infection [51,52]. The potential protective effect of HIV-2 infection against subsequent HIV-1 challenge requires further study, as the mechanisms underlying such protection could prove valuable in the design of a protective vaccine against HIV-1. Although some encouraging work has been carried out in the area of vaccine development using HIV-2 [53-56], much work remains to be done. Currently, only two candidates for an HIV vaccine are in phase III clinical trials, both based on HIV-1 viral isolates (reviewed in [57], updated information available on www.niaid.nih.gov/daids/vaccine/statuslinks.htm). More investigation into HIV-2-based vaccines, as well as further determination of any HIV-2-mediated protection against subsequent HIV-1 challenge, is called for. Co-receptor use Like HIV-1, HIV-2 has been shown to use CD4 cells as a primary receptor, and several chemokine receptors as co-receptors, for infection of target cells [58]. HIV-1 uses either CCR-5 or CXCR-4 as the major co-receptors for infection [59-62], but can also use other molecules to a lesser extent, such as CCR3 [58]. SIV preferentially uses CCR5 and, occasionally, CXCR4 [63,64]. Surprisingly, considering its lesser pathogenicity, HIV-2 appears to be more flexible in co-receptor usage than is HIV-1. Several HIV-2 strains have been shown to infect certain CD4-negative cell lines, most by using CXCR-4 or CCR-5 alone [65-68], and are better at doing so than is HIV-1. Primary HIV-2 isolates, unlike HIV-1, have also been found to use multiple different co-receptors such as CXCR-4, CXCR5/BLR1, CCR-1, CCR-2b, CCR-3, CCR-4, CCR-5, CCR-8, V28, BOB/GPR15, Bonzo/STRL33, APJ, and US28 for either infection, cell-cell fusion, or both. Unlike HIV-1, most primary HIV-2 isolates tested can productively infect Δ32/Δ32 CCR5 PBMC [64,69,70]. Even though HIV-2 isolates can make use of alternative co-receptors, CCR-5 and CXCR-4 still appear to be the dominant co-receptors used [58,64,69-75]. HIV-2 transcriptional regulation The HIV long terminal repeat contains the promoter and enhancer, in which are found cis-acting elements that respond to T-cell or monocyte activation and play a role in the regulation of viral transcription. HIV-1 isolates in the West (HIV-1B) contain two regulatory elements that bind the transcription factor nuclear factor-κB (NF-κB) and enhance HIV-1 transcription, whereas HIV-1C (prevalent in sub-Saharan Africa and India) contains three HIV-2 contains only one such as The of the HIV-1, but not the HIV-2, However, HIV-2 contains other elements not found in HIV-1. These the and which are to of the of the T-cell complex and bind the family and the which the nuclear of any of these elements the response of the to cellular activation at the RNA level but not the response to Tat or to other viral proteins the HIV-1 but only that of HIV-2 a identified in the of HIV-2 and SIV isolates but not of HIV-1, activation of cell lines but not T-cell lines which on an RNA response element (TAR) of the transcriptional to enhance transcriptional and, also between HIV-1 and HIV-2. HIV-1 and HIV-2 TAR both respond to HIV-1 whereas HIV-2 Tat can generally only through HIV-2 TAR HIV-1 TAR RNA contains one structure, HIV-2 TAR RNA contains two or three (reviewed in HIV-2 TAR can HIV-1 replication, presumably by to HIV-1 Tat cellular and inhibiting their interaction with HIV-1 TAR [45,46]. infection, HIV within an cell is for a of cellular replication of the virus cellular such as immune activation viral clinical is associated and an in viral replication, in the transcriptional activity of HIV-1 and HIV-2 in responsible for some of the in viral and clinical later) between these two HIV-2 proteins the sequence HIV-2 the same gene as HIV-1. Like all HIV-1, HIV-2, and SIV the gag pol and env The env gene from to in HIV-2, it the of the and the In both HIV-1 and HIV-2, the CD4 cell and chemokine co-receptors The gag gene and pol the and The gag and pol are well in HIV-1, HIV-2, and SIV, and for most seen in for HIV-1 [7]. In to and HIV-1, HIV-2 and SIV contain additional in for the gene and is known concerning in and between HIV-1 and HIV-2, for these proteins have been described in HIV-1 infection (reviewed in While HIV-1 HIV-2 and SIV with CD4 by to CD4 in the and it for The decrease in CD4 protect cells against and for of viral The gene is also for virus independent of its CD4 activity and has been shown to with the of major complex molecules The vpx and are to have from a common as are highly similar in sequence The vpx and are that are for infection and replication in cell lines in but are to various for infection and replication and PBMC are and with the gag gene are also highly and vpx is in both HIV-2 and SIV Although similar in HIV-1 and HIV-2 appear to in their in the infected HIV-1 can to in cells and from HIV-1, HIV-2, and SIV can all in and cell lines Unlike HIV-1 HIV-2 is in viral vpx is into HIV-2 To infect for nuclear HIV-1 and HIV-2 vpx are for nuclear of the viral complex and as such are for infection and replication in PBMC and not in T-cell lines or previously PBMC HIV-2 not appear to be for infection of unlike HIV-1 HIV-2 vpx the for such infection of vpx from HIV-2 a virus for replication in SIV isolates of either or vpx alone could still a the virus of HIV-2 HIV-2 appears to be transmitted in West Africa by or by with infected blood HIV-2 transmission appears to from that of HIV-1 in two HIV-2 is less readily transmitted by sexual than is HIV-1 of transmission of HIV-2 is to be lower than that of HIV-1 rates of HIV-2 infection with increasing in both men and a lower transmission rate than for HIV-1, with the rate of viral in samples was shown to be in HIV-2-positive with in some of the in rates of transmission transmission from infected to during or through is much less with HIV-2 than with HIV-1 Although transmission in approximately of most studies have shown that transmission of HIV-2 of all HIV-2-positive In one study, infected with both HIV-1 and HIV-2 transmitted HIV-1 to their but in only one was HIV-2 transmitted this with is HIV-2 less pathogenic than HIV-1? HIV-2 AIDS but the between infection and development of AIDS appears to be than that for HIV-1 in disease in be due to lower viral loads in those infected with HIV-2 than in those infected with HIV-1 However, disease patients with HIV-2 generally have most of the same and as HIV-1 HIV-1 infection, the of clinical to AIDS appears to be the level of as by HIV-1 long-term who have and stable CD4 cell for at least years to have of RNA of lower than more While the majority of HIV-2-infected individuals much than this between and to AIDS in HIV-2 infection as In the rate for than years of infected with HIV-2 uninfected individuals was whereas for older people was much to 1 not with and, in most infection with HIV-2 not survival the of two one that and of and the who long-term A similar was with viral in a study by et no was found between viral and high or low CD4 cell in transmission and clinical between HIV-2 and HIV-1 be at least in by in viral disease and higher viral loads have been with transmission of HIV-2 HIV-2 infection to much lower of at all of disease and of T with a viral generally lower than that of HIV-1 The viral infection is lower in HIV-2-positive patients as with patients [39]. viral loads are with decreasing CD4 cell in both HIV-1 and HIV-2 infection CD4 cell are further with disease in both HIV-1 and HIV-2 infection into target appears to be similar between HIV-1 and HIV-2, even for clinical In HIV-2, is found with CD4 cell and directly associated with disease However, of and viral RNA were not in subjects Thus, while HIV-1 and HIV-2 infection to similar of or infected target viral replication, and thus is very much lower in HIV-2 than in HIV-1. that in be at least in to in RNA from the than to an in the of in HIV-2 and HIV-1 transcriptional regulation could thus for some of the in viral between HIV-1 and HIV-2. HIV-2 infection to a higher of viral to As viral has a on clinical for these between HIV-1 and HIV-2 appear to be While in viral and disease HIV-2, as with HIV-1, infection be due at least in to viral transcription and replication other are also at in the ability of HIV-2 and HIV-1 to cells and to an immune response have been reported (reviewed in least two groups have reported lower rates of T-cell associated with HIV-2 infection than with HIV-1 infection As has been very reviewed in studies have shown that HIV-2 a and cellular immune with what appears to be a neutralizing antibody response and more than is seen with HIV-1. Thus, the lesser of HIV-2 be due to a lower rate of viral replication a immune either or both of which could to a lower viral to the lesser of by HIV-2. of HIV-2 infection Although HIV-2 disease more to AIDS in HIV-2-infected people with a similar of and as in both in and of HIV-2 infection disease of greater than body and or for greater than 1 infected with HIV-2 of the of of HIV-2 infection with HIV-1 infection in similar to be and infection The major of among HIV-2 AIDS patients are and of Although similar in clinical to HIV-1, HIV-2 disease show some HIV-2 not appear to be associated with increasing rates of clinical or is at least less so than is HIV-1 infection, HIV and were all found to be more in AIDS than in that associated with HIV-1. As these three are generally associated with in HIV-1 disease this that HIV-2-infected patients in the terminal of infection As with CD4 cell and lymphocyte are decreased as with as is the cell However, these decreases are not as as in HIV-1 disease In addition, HIV-2 infection to decreases in lymphocyte (a of to and which are similar but less dramatic the seen with HIV-1 infection HIV-2-positive subjects to be older than subjects this is due to HIV-2-positive people than a a for more to HIV-2 or a of these is a common in AIDS patients in the United States to the use of highly is an disease in and is associated with infection by the virus called virus) Infection with HIV-1 the for However, an between and HIV-2 has not been In western Africa, no in the incidence of has been a high incidence of HIV-2 infection Even among HIV-2 AIDS cases of have been HIV-1 HIV-2 infection, the for has been to be similar of virus in the two groups have that the HIV-1 viral Tat is an due to an within the which HIV-2 Tat and HIV-2 is to in and in but be less so than is HIV-1 the use of a nucleotide this has been demonstrated to as within of exposure to HIV-2 in a HIV-2 is not to due to found within the of the In one study, primary HIV-2 isolates at least one associated with resistance in HIV-1, and most had two In HIV-2 generally appear to be to in of the exact in activity of these is more difficult with HIV-2 than with HIV-1 is no and to HIV-2 viral lower of are often found in HIV-2 patients as with those with HIV-1 low to and most HIV-2-infected people in West Africa, to is study the of an HIV-2-infected with and showed both an in CD4 cells and a decrease in HIV-2 in PBMC the of However, as is the with HIV-1, resistance to both and can while on for HIV-2 More studies at in are to for HIV-2-infected of infections in HIV-2-infected patients appears to be more than in those with HIV-1 infection very data about of in HIV-2 patients As CD4 cell in HIV-2 disease appear to the of it to on CD4 cell as is for HIV-1. However, people with HIV-2 infection a less for long-term than people with HIV-1. Studies to these however, exact can be to the in the clinical of HIV-2 with HIV-1, it that a more can be HIV-2-infected any of of clinical with and in patients with HIV-2. As with these patients be to any sexual of their use such as or sexual contact, and not to blood or in any activity that to their blood of or In of the low rate of and the lower in the HIV-2-infected a much lower to the in of infection, and also a lower for the an than in the Based on the data with HIV-1, demonstrating a drop in infection rates with of and we similar of HIV-2-infected and their for the of to the and the with also Although some are being evaluated for use in due to the resistance demonstrated by HIV-2 to we against use of such in HIV-2-infected pregnant Although less than HIV-1, HIV-2 remains an in western Africa, as well as in Portugal and some countries by the Although similar to HIV-1, HIV-2 also has distinct biological AIDS is similar to that caused by HIV-1, significant between HIV-2 and HIV-1 in to disease with and transmission rate with as well as in viral transcriptional regulation and for HIV-2 has not been well Based on studies and very clinical and by from HIV-1 clinical studies, it appears that patients with HIV-2 infection and low CD4 cell from with and but not of infections in HIV-2 not well be in a similar to that in HIV-1 for infections prove to be less with HIV-2 than HIV-1 infection, but it to any on CD4 cell Furthermore, studies the in HIV-2 and HIV-1 infection, replication, and transmission of as the information could significantly on for and development of against both HIV-2 and HIV-1 infection. The like to and for their on the