Proviral Progeny of Heterodimeric Virions Reveal a High Crossover Rate for Human Immunodeficiency Virus Type 2

Abstract

Human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS in humans, exhibits a very high rate of recombination. Bearing in mind the significant epidemiological and clinical contrast between HIV-2 and HIV-1 as well as the critical role that recombination plays in viral evolution, we examined the nature of HIV-2 recombination. Towards this end, a strategy was devised to measure the rate of crossover of HIV-2 by evaluating recombinant progeny produced exclusively by heterodimeric virions. The results showed that HIV-2 exhibits a crossover rate similar to that of HIV-1 and murine leukemia virus, indicating that the extremely high rate of crossover is a common retroviral feature.Human immunodeficiency virus type 1 (HIV-1) exhibits significant genetic diversity, which allows it to constantly evade the host immune response, to circumvent antiretroviral therapy, and to erect barriers to the development of an effective vaccine (3, 23). The molecular basis for such diversity lies in the error-prone nature of the virally encoded reverse transcriptase (RT) (16) and the ability of RT to switch templates (27). Together, these mechanisms generate viral variants at a high rate and represent a major force in driving HIV-1 evolution in infected populations worldwide. Previous studies from our laboratory and others have shown that HIV-1 exhibits a high rate of recombination, averaging between three and four crossovers per cycle of replication (10,20,29). It has been reported to be significantly higher when macrophages were used as targets (14). This high rate of recombination is not surprising in the context of the 16 circulating recombinant forms that have been recorded so far from patient samples worldwide (13).It is hypothesized that, like HIV-1, HIV-2 arose by zoonotic transmission from simian immunodeficiency virus-infected primates to humans and while HIV-1 is responsible for the global AIDS epidemic, HIV-2 has remained largely restricted to West Africa, certain parts of Europe, and some parts of southwestern India (18, 26). Although they are very similar in the genomic organization and biological functions of their gene products, their sequences diverge by approximately 50% at the nucleotide level (8,15,22). Overall, HIV-2 differs from HIV-1 in having (i) lower rates of horizontal and vertical transmission (2, 11, 17), (ii) reduced pathogenicity (4), (iii) considerable CD4-independent tropism (19), and (iv) longer clinical latency periods (1, 5). In spite of its restricted geographical distribution, recombinant strains of HIV-2 have been reported in West Africa. These chimeric viruses include both intra-and intergroup (subtypes A and B) recombinants (7,21). In this study we aimed at measuring the crossover rate of HIV-2 by using a strategy that selectively scores for progeny of heterodimeric virions. Moreover, by using the same strategy, experiments with HIV-1 were conducted in parallel to further validate our findings. Also, the significance of a high crossover rate to the basic mechanism of retroviral reve...

The Remarkable Frequency of Human Immunodeficiency Virus Type 1 Genetic Recombination

“…For both HIV-1 and gammaretroviruses, reducing RNase H activity decreased template switching (37,234). These findings suggested that retroviruses with low RNase H activity, such as HIV-2 (132), would recombine less frequently than HIV-1, which possesses robust RNase H. However, subsequent studies demonstrated that rates of template switching are very similar for HIV-2 and HIV-1 (50,221).…”

“…Other evidence comes from observations that recombination is fully as frequent when only minus-strand recombination is possible as when both minus-and plus-strand recombination could contribute (12,148,355,359). Another argument against significant plus-strand recombination lies in the very high frequency of minus-strand crossovers, because the template degradation which that would require precludes extensive plus-strand diploidy (221). Nonetheless, "backwards" insertions have been observed for both experimental replication products and clinical isolates (87, 311; see discussion in reference 314).…”

“…It was thought that the performance of one recombination event predisposed a virus to performing additional switches or that only a subset of virions was prone to generating recombinant products due to flaws in viral nucleoprotein complex architecture (15,133,152). However, biases in gRNA packaging remove the need to evoke such models and suggest that recombination occurs at a similar high frequency for many if not all retroviruses (50,221,240,368). This can also explain differences between MLV and HIV-1 in minus strong-stop switching.…”

Genetic Recombination between Human Immunodeficiency Virus Type 1 (HIV-1) and HIV-2, Two Distinct Human Lentiviruses

“…Recombination can occur between highly related viruses to reassort sequences, thereby increasing the diversity of the population and allowing the emergence of variants that are most fit for the particular selection pressures at a given time (2,11,13,16,27,28,33,37,(39)(40)(41)47). Recombination can also occur between genetically similar viruses that are further apart in sequence identity than those in a viral population.…”