| |
APOBEC3G, hA3G expression affects the establishment of the viral set point and may therefore function as a host determinant in the pathogenesis of HIV-1 infection, developing AIDS more quickly
|
| |
| |
"Further studies are needed to elucidate how APOBEC proteins are regulated and to shed light on how APOBEC might be incorporated in novel prophylactic and therapeutic interventions.....In conclusion, this study supports the hypothesis that hA3G and hA3F may be important host factors in the pathogenesis of HIV-1 infection. We show that hA3G mRNA is significantly correlated with establishment of the viral set point and that there is an increase in expression of hA3G and hA3F after HIV-1 infection. The magnitude of increase for both hA3G and hA3F was significantly greater in the low viral set point group. The increase in expression of hA3G and hA3F after infection suggests that these 2 proteins might be part of an innate immune response against HIV-1 infection."
Relationship between Human Immunodeficiency Type 1 Infection and Expression of Human APOBEC3G and APOBEC3F
The Journal of Infectious Diseases Aug 15 2008;198:486-492
Nzovu K. Ulenga, Abdoulaye Dieng Sarr, Seema Thakore-Meloni, Jean-Louis Sankale, Geoff Eisen, and Phyllis J. Kanki
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts
ABSTRACT
Background. Human immunodeficiency virus type 1 (HIV-1)-infected individuals with a high viral set point progress to acquired immunodeficiency syndrome (AIDS) more rapidly than those with a low viral set point. It is not entirely clear which host and viral factors are responsible for the viral set point. Host factors that affect virus replication are likely to influence the viral set point. Human APOBEC proteins have been shown to restrict HIV-1 replication.
Methods. This prospective study was conducted to determine the relationship between human APOBEC3G (hA3G) and APOBEC3F (hA3F) levels and the viral set point. Fourteen subjects were classified as having a high viral set point, and 16 were classified as having a low viral set point. We quantified the levels of hA3G and hA3F mRNA in HIV-1-infected, antiretroviral drug-naive individuals before and after infection.
Results. We found a significant correlation between the hA3G mRNA level and the viral set point. The expression of hA3G and hA3F increased after infection, and the levels of hA3G and hA3F mRNA were significantly higher after infection in the low viral set point group, compared with the high viral set point group.
Conclusions. The results suggest that the level of hA3G expression affects the establishment of the viral set point and may therefore function as a host determinant in the pathogenesis of HIV-1 infection.
The progression of human immunodeficiency virus type 1 (HIV-1) infection to disease has a highly variable duration. Although the median time to development of acquired immunodeficiency syndrome (AIDS) is 8 years, some patients develop AIDS in <3 years, whereas others remain healthy without symptoms for >15 years [1-3]. The reasons for these differences are not fully understood, but the differences are thought to result from the interaction of virus and host factors. For example, heterozygosity of class 1 loci (A, B, and C) delayed progression to AIDS, whereas homozygosity was associated with rapid progression to AIDS [4, 5]. Early HIV-1 infection is characterized by an initial period during which the rate of viral replication is high, leading to very high virus loads 2 months after infection, followed by a 6-9-month period during which the virus load decreases until achievement of a steady state level, commonly referred to as the viral set point, which is a strong predictor of disease progression [6-8]. Individuals with a high viral set point have been shown to progress to AIDS more rapidly than individuals with a low viral set point [9-11]. The viral set point is thought to be determined by the breadth of HIV-specific immune responses and the extent of viral replication [12].
Ongoing viral replication is considered an important factor in the determination of the viral set point because the composite life span of the virus and virus-producing cells is very short (half-life, 2 days) [13]. In viral dynamics studies by Wei et al. [13], total replacement of wild-type circulating virus in plasma with drug-resistant strains occurred after only 2 weeks, indicating that the HIV-1 viral set point is sustained by a dynamic process that includes continuous rounds of virus infection, replication, and rapid cell turnover [13, 14]. Therefore, any host or viral factor that influences HIV-1 replication likely has an impact on the viral set point.
Two recently discovered host restriction factors in humans, APOBEC3G (hA3G) and APOBEC3F (hA3F), have been shown to restrict HIV-1 replication in vitro [15-20]. hA3G and hA3F exist in 2 forms in the cell, a high-molecular-mass complex and a low-molecular-mass complex; the antiviral activity of the proteins is associated with levels of the low-molecular-mass complexes [21-23]. Moreover, high levels of hA3G mRNA correspond to high levels of high-molecular-mass complex, low-molecular-mass complex, and hA3G-associated antiviral activities [24]. Interestingly, the HIV-1 virion infectivity factor (Vif) has been demonstrated to negatively influence the antiviral activities of hA3G and hA3F [25]. When Vif levels are low or Vif is absent, hA3G and hA3F incorporate into virions and catalyze cytidine deamination, leading to hypermutation from G to A in the viral genome [16, 26, 27]. HIV-1 Vif, in turn, inhibits hA3G and hA3F by inducing their proteosomal degradation and preventing their incorporation into virions.
On the basis of these observations, we hypothesized that high levels of hA3G and hA3F might overcome the neutralizing effects of HIV-1 Vif and reduce the rate of viral replication, decreasing the viral set point. In this study, we explore whether these 2 proteins play a role in determining the viral set point upon HIV-1 infection.
Levels of hA3G and hA3F mRNA in HIV-1-infected individuals are lower than in uninfected individuals [28]. In contrast, other studies showed that hA3G expression is higher in HIV-1-exposed seronegative individuals than in healthy controls and that long-term nonprogressors express a higher level of hA3G than rapid progressors [29, 30] . However, it is not known whether the levels of hA3G and hA3F increase or decrease upon HIV-1 infection or whether host factors establish the levels. To determine the effect of HIV-1 infection on expression of hA3G and hA3F, we characterized expression of these host restriction factors before and after HIV-1 infection.
Discussion
The role of hA3G and hA3F proteins in restricting HIV-1 replication in vivo has been suggested in previous studies [34, 35]. In vivo studies have supported in vitro observations in which hA3G mRNA levels in PBMCs were higher in long-term nonprogressors than in progressors. Because the viral set point correlates with the rate of disease progression [9], we investigated whether there was any relationship between the levels of hA3G and hA3F expression and the viral set point. We found an intriguing relationship between the levels of both hA3G and hA3F mRNA transcripts and the viral set point in the HIV-1-infected individuals we studied.
There was an inverse relationship between the levels of hA3G and hA3F mRNA and the viral set point after HIV-1 infection. The levels of hA3G and hA3F mRNA after infection in the low viral set point group were higher than in the high viral set point group (p=.020 for hA3G and p=.022 for hA3F, by the Mann-Whitney U test). Our results support previous findings that HIV-1-infected individuals with high viremia expressed less hA3G mRNA than those with low viremia [35]. This inverse relationship between viremia and APOBEC (hA3G and hA3F) expression suggests a role of APOBEC proteins in controlling viremia.
We further explored the association between viral set point and APOBEC mRNA, using univariate and multivariate linear regression (table 1). There was a statistically significant inverse correlation between the level of hA3G and the viral set point (table 1), associating hA3G with the pathogenesis of HIV-1 infection. These results complement the recent work of Mallal et al. [36], who investigated the effect of hA3G- and hA3F-mediated HIV-1 sequence hypermutation on pretreatment viremia. Their study showed that patients with hypermutated sequences had significantly lower virus load than those with nonhypermutated sequences, even after adjustment for the CD4+ cell count and the human leukocyte antigen profile. In another study, Jin et al. [35] linked hA3G to the virus load in an examination of an abundance of hA3G mRNA in primary human cells isolated from patients infected with HIV-1. This study found that the levels of hA3G mRNA are higher in long-term nonprogressors (who have a low virus load) than in progressors (who have a high virus load). Our findings and the observations described above support in vitro studies that demonstrated that hA3G and hA3F can still mutate HIV-1 sequences, even if a functional Vif is present [37, 38]. These observations implicate hA3G as a clinically relevant host restriction factor that may play a role in determining the pathogenesis of HIV-1 infection.
The association between hA3G and the pathogenesis of HIV-1 infection might be due to the fact that hA3G restricts HIV-1 replication [17-19, 34, 39]. Therefore, it is possible that high levels of hA3G inhibit the replication rate of HIV-1, both before and after the onset of specific immune responses, thus contributing to a decrease in the viral set point. Furthermore, low replication rates in individuals with a high level of hA3G expression might limit viral diversity and, therefore, enhance the efficacy of adaptive immunity in clearing viruses, resulting in a low viral set point [40-42].
Apart from showing a difference in expression of hA3G and hA3F between the low and high viral set point groups, this study also revealed an increase in the levels of both hA3G and hA3F mRNA upon HIV-1 infection in each study group. The increase in expression of hA3G was significantly higher in the low viral set point group (p=.041, by the Mann-Whitney U test).
Viral regulation of hA3G expression has been reported previously by Komohara et al. [43], who recently showed that individuals who were hepatitis C virus (HCV) positive expressed more hA3G than those who were HCV negative. Another recently published report showed that the expression of hA3G was significantly increased in HIV-exposed seronegative individuals, compared with healthy control subjects [44]. It is not clear, however, whether the increase in hA3G in this study was brought about by HIV exposure or whether the individuals naturally expressed high levels of hA3G as a predetermined host factor. Our study demonstrates for the first time that the expression of both hA3G and hA3F increase upon HIV-1 infection, especially in individuals who develop a low viral set point. The increase in expression seems to be triggered by either infection with or exposure to HIV-1, but it is not proportional to the virus load, as evidenced by the larger increase in expression of hA3G and hA3F in the low viral set point group, compared with the high viral set point group. Interestingly, the level of interferon-β (IFN-β) has been shown to increase upon HIV-1 infection in some individuals [24, 45-47]. Because IFN-β elevates the levels of hA3G and hA3F expression [24, 48-50], increased levels of this cytokine may be responsible for the observed increase in expression of hA3G and hA3F.
In conclusion, this study supports the hypothesis that hA3G and hA3F may be important host factors in the pathogenesis of HIV-1 infection. We show that hA3G mRNA is significantly correlated with establishment of the viral set point and that there is an increase in expression of hA3G and hA3F after HIV-1 infection. The magnitude of increase for both hA3G and hA3F was significantly greater in the low viral set point group. The increase in expression of hA3G and hA3F after infection suggests that these 2 proteins might be part of an innate immune response against HIV-1 infection. Further studies are needed to elucidate how APOBEC proteins are regulated and to shed light on how APOBEC might be incorporated in novel prophylactic and therapeutic interventions.
|
|
| |
| |
|
|
|
