We previously reported finding the RNA of a type K human endogenous retrovirus, HERV-K (HML-2), at high titers in the plasma of HIV-1-infected and cancer patients (R. Contreras-Galindo et al., J. Virol. 82:9329 -9236, 2008.). The extent to which the HERV-K (HML-2) proviruses become activated and the nature of their activated viral RNAs remain important questions. Therefore, we amplified and sequenced the full-length RNA of the env gene of the type 1 and 2 HERV-K (HML-2) viruses collected from the plasma of seven HIV-1-infected patients over a period of 1 to 3 years and from five breast cancer patients in order to reconstruct the genetic evolution of these viruses. HERV-K (HML-2) RNA was found in plasma fractions of HIV-1 patients at a density of ϳ1.16 g/ml that contained both immature and correctly processed HERV-K (HML-2) proteins and virus-like particles that were recognized by anti-HERV-K (HML-2) antibodies. RNA sequences from novel HERV-K (HML-2) proviruses were discovered, including K111, which is specifically active during HIV-1 infection. Viral RNA arose from complete proviruses and proviruses devoid of a 5= long terminal repeat, suggesting that the expression of HERV-K (HML-2) RNA in these patients may involve sense and antisense transcription. In HIV-1-infected individuals, the HERV-K (HML-2) viral RNA showed evidence of frequent recombination, accumulation of synonymous rather than nonsynonymous mutations, and conserved N-glycosylation sites, suggesting that some of the HERV-K (HML-2) viral RNAs have undergone reverse transcription and are under purifying selection. In contrast, HERV-K (HML-2) RNA sequences found in the blood of breast cancer patients showed no evidence of recombination and exhibited only sporadic viral mutations. This study suggests that HERV-K (HML-2) is active in HIV-1-infected patients, and the resulting RNA message reveals previously undiscovered HERV-K (HML-2) genomic sequences.

Approximately 8% of the human genome sequence is composed by human endogenous retroviruses (HERVs), most of which are defective. HERV-K(HML-2) is the youngest and most active family and has maintained some proviruses with intact open reading frames (ORFs) that code for viral proteins that may assemble into viral particles. Many HERV-K(HML-2) sequences are polymorphic in humans (present in some individuals but not in others) and probably many others may be unfixed (not inserted permanently in a specific chromosomal location of the human genome). In the present study HIV-1 and HCV-1-positive plasma samples were screened for the presence of HERV-K(HML-2) RNA in an RT-PCR using HERV-K pol specific primers. HERV-K(HML-2) viral RNA sequences were found almost universally in HIV-1(+) plasma samples (95.33%) but were rarely detected in HCV-1 patients (5.2%) or control subjects (7.69%). Other HERV-K(HML-2) viral segments of the RNA genome including gag, prt, and both env regions, surface (su), and transmembrane (tm) were amplified from HERV-K pol-positive plasma of HIV-1 patients. Type 1 and type 2 HERV-K(HML- 2) viral RNA genomes were found to coexist in the same plasma of HIV-1 patients. These results suggest the HERV-K(HML-2) viral particles are induced in HIV-1-infected individuals.

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The viral kinetics of HERV-K in HIV-1-infected patients receiving highly active antiretroviral therapy (HAART) is not unknown. HERV-K kinetic modeling may provide insight into factors altering the effectiveness of HAART in suppressing HIV-1 burden. We conducted a longitudinal study measuring the HERV-K RNA titers in four patients with successful HIV-1-suppressive HAART and in six patients undergoing HAART failure. HERV-K titers were usually undetectable in patients with successful HAART, and when detected, HERV-K titers remained below 5000 copies/ml. On the other hand, HERV-K RNA was consistently detected in patients who failed to respond to HAART before and after HIV-1 rebounds (p < 0.001). Elevated HERV-K RNA titers frequently preceded HIV-1 rebounds. These results suggest that HERV-K viral load may predict HIV-1 reactivation. HERV-K RNA testing might be clinically useful in predicting the onset of HIV-1 resistance due to suboptimal antiretroviral drug levels and/or poor adherence to treatment.

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