Frequent Intrapatient Recombination between Human Immunodeficiency Virus Type 1 R5 and X4 Envelopes: Implications for Coreceptor Switch

Abstract

Emergence of human immunodeficiency virus type 1 (HIV-1) populations that switch or broaden coreceptor usage from CCR5 to CXCR4 is intimately coupled to CD4؉ cell depletion and disease progression toward AIDS. To better understand the molecular mechanisms involved in the coreceptor switch, we determined the nucleotide sequences of 253 V1 to V3 env clones from 27 sequential HIV-1 subtype B isolates from four patients with virus populations that switch coreceptor usage. Coreceptor usage of clones from dualtropic R5X4 isolates was characterized experimentally. Sequence analysis revealed that 9% of the clones from CXCR4-using isolates had originated by recombination events between R5 and X4 viruses. The majority (73%) of the recombinants used CXCR4. Furthermore, coreceptor usage of the recombinants was determined by a small region of the envelope, including V3. This is the first report demonstrating that intrapatient recombination between viruses with distinct coreceptor usage occurs frequently. It has been proposed that X4 viruses are more easily suppressed by the immune system than R5 viruses. We hypothesize that recombination between circulating R5 viruses and X4 viruses can result in chimeric viruses with the potential to both evade the immune system and infect CXCR4-expressing cells. The broadening in cell tropism of the viral population to include CXCR4-expressing cells would gradually impair the immune system and eventually allow the X4 population to expand. In conclusion, intrapatient recombination between viruses with distinct coreceptor usage may contribute to the emergence of X4 viruses in later stages of infection.

The Remarkable Frequency of Human Immunodeficiency Virus Type 1 Genetic Recombination

“…Thus, experimental rates of recombination can be compared to clinical outcomes to help assess selective forces. For example, an analysis of intrapatient recombination between the R5 and X4 env genes revealed evidence of a coreceptor switch resulting from two recombinogenic template switches occurring within 240 bases in env (212), much closer than predicted by average crossover rates but likely detected because of phenotypic selection. The appearance of such variants is likely possible because the very high frequency of crossing over per replication cycle, paired with the estimated ϳ10 10 virions produced per day, provides HIV-1 with an almost infinite combinatorial potential (252).…”

“…Because two different defective retroviruses can recombine to form infectious virus, even defective genomes can contribute to the reemergence of dormant genetic information. Intrapatient recombination between circulating strains and archived proviruses contributes to the dynamics of drug resistance and may contribute to the evolution of the coreceptor switch as well (47,118,212,235,271). It is likely that the extent of recombination between variants that arise within an individual has been underappreciated because of the similarity of parental strains (117).…”

“…(Hypermutation may be an exception to this rule, although whether such mutations imbedded in less altered genome regions result more frequently from recombination or from the limited processivity of mutagenic factors remains unclear [48,222,236].) Some instances of phenotypic switch, including coreceptor switch and reacquisition of drug resistance, have been linked to mutations embedded in localized sequences that differ significantly from flanking sequences, thus providing evidence for recombination within individual patients' virus populations (118,212,235,271).…”

The Changing Trends of HIV Subtypes and Its Implication on Mother-to-Child Transmission

“…These point mutations are base-pair substitutions, and base-pair insertions or deletions. Recombination occurs frequently during reverse transcription, a consequence of having two RNA genomes packaged per virion 11 . A significant fraction of the HIV-1 group M global diversity includes interclade viral recombinants ( Figure 1).…”

Risks from GMOs due to Horizontal Gene Transfer

“…In the short term, HGT can increase genetic diversity and promote the spread of novel adaptations between organisms (Marri et al, 2007;Thomason and Read, 2006). HGT has been a major contributory factor to the rapid spread of antibiotic resistance amongst pathogenic bacteria in the last 50 years (Mazel and Davies, 1999), and the emergence of increased virulence in bacteria, eukaryotes and viruses (Derbise et al, 2007;Friesen et al, 2006;Mild et al, 2007). In the long term it has been proposed that HGT has contributed to the major transitions in evolution (Koonin, 2007).…”