The calculated genetic barrier for antiretroviral drug resistance substitutions is largely similar for different HIV-1 subtypes.

BACKGROUND: The genetic barrier, defined as the number of mutations required to overcome drug-selective pressure, is an important factor for the development of HIV drug resistance. Because of high variability between subtypes, particular HIV-1 subtypes could have different genetic barriers for drug resistance substitutions. This study compared the genetic barrier between subtypes using some 2000 HIV-1 sequences (>600 of non-B subtype) isolated from anti-retroviral-naive patients in Europe. METHODS: The genetic barrier was calculated as the sum of transitions (scored as 1) and/or transversions (2.5) required for evolution to any major drug resistance substitution. In addition, the number of minor protease substitutions was determined for every subtype. RESULTS: Few dissimilarities were found. An increased genetic barrier was calculated for I82A (subtypes C and G), V108I (subtype G), V118I (subtype G), Q151M (subtypes D and F), L210W (subtypes C, F, G, and CRF02_AG), and P225H (subtype A) (P < 0.001 compared with subtype B). A decreased genetic barrier was found for I82T (subtypes C and G) and V106M (subtype C) (P < 0.001 vs subtype B). Conversely, minor protease substitutions differed extensively between subtypes. CONCLUSIONS: Based on the calculated genetic barrier, the rate of drug resistance development may be similar for different HIV-1 subtypes. Because of differences in minor protease substitutions, protease inhibitor resistance could be enhanced in particular subtypes once the relevant major substitutions are selected.

Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management.

BACKGROUND: Infection with drug-resistant human immunodeficiency virus type 1 (HIV-1) can impair the response to combination therapy. Widespread transmission of drug-resistant variants has the disturbing potential of limiting future therapy options and affecting the efficacy of postexposure prophylaxis. METHODS: We determined the baseline rate of drug resistance in 2208 therapy-naive patients recently and chronically infected with HIV-1 from 19 European countries during 1996-2002. RESULTS: In Europe, 1 of 10 antiretroviral-naive patients carried viruses with > or = 1 drug-resistance mutation. Recently infected patients harbored resistant variants more often than did chronically infected patients (13.5% vs. 8.7%; P=.006). Non-B viruses (30%) less frequently carried resistance mutations than did subtype B viruses (4.8% vs. 12.9%; P<.01). Baseline resistance increased over time in newly diagnosed cases of non-B infection: from 2.0% (1/49) in 1996-1998 to 8.2% (16/194) in 2000-2001. CONCLUSIONS: Drug-resistant variants are frequently present in both recently and chronically infected therapy-naive patients. Drug-resistant variants are most commonly seen in patients infected with subtype B virus, probably because of longer exposure of these viruses to drugs. However, an increase in baseline resistance in non-B viruses is observed. These data argue for testing all drug-naive patients and are of relevance when guidelines for management of postexposure prophylaxis and first-line therapy are updated.

Vaccination of C57/BL6 mice with Dobrava hantavirus nucleocapsid protein in Freund's adjuvant induced partial protection against challenge.

Dobrava hantavirus (DOBV) causes a severe form of hemorrhagic fever with renal syndrome (HFRS) for which there is no therapy or vaccine available. We compared the immunogenicity and protective efficacy of recombinant DOBV nucleocapsid protein (rDOBV N) given with Alum or Freund's as adjuvant, or PBS, in C57/BL6 mice. All mice given Alum or Freund's seroconverted as did 6/8 mice given rDOBV N with PBS. Reciprocal geometric mean total IgG-titers were 5380, 18,100, and 800, respectively, while the mean IgG1/IgG2a ratios were 17.5, 9.25, and 12, respectively. Furthermore, ELIspot assays showed higher levels of IL-4 producing peripheral blood mononuclear cells (PBMCs) in the group given Alum as compared to the other groups. Interestingly, only mice receiving rDOBV N with Freund's adjuvant were protected from challenge (75% protected), indicating that the strong Th2-type of immune response induced by Alum against rDOBV N did not induce protection in mice.

HIV-1 CRF01_AE in intravenous drug users in Hanoi, Vietnam.

To investigate the molecular epidemiology of HIV-1 among intravenous drug users (IDUs) in Hanoi we collected 17 samples from individuals living in 12 locations in and around Hanoi. The HIV-1 env V3 and gag p17 regions were directly sequenced from the proviral PBMC population. The majority of the IDUs were infected with HIV-1 CRF01_AE and one individual carried a p17/V3 CRF01/subtype C recombinant. The CRF01 viruses found among these individuals did not seem to be directly epidemiologically linked to each other. The sequences were, however, related to previously reported CRF01 sequences from Vietnam and China. Thus, IDUs in Hanoi seem to have derived their infections in Vietnam, but not from the same source. The discovery of the CRF01/C recombinant shows that new viral forms easily can be generated in IDU transmission chains.

Limited transmission of drug-resistant HIV type 1 in 100 Swedish newly detected and drug-naive patients infected with subtypes A, B, C, D, G, U, and CRF01_AE.

The prevalence of genetic drug resistance in newly diagnosed HIV-1 cases and potential subtype-specific mutation patterns were studied. Samples from 100 newly diagnosed patients were randomly chosen from three HIV clinics in Sweden, prospectively collected during the period June 1998 to August 2001. Viral RNA was extracted from plasma and an approximately 2000-bp fragment covering the protease (PR) and reverse transcriptase (RT) genes was sequenced. Subtypes A, B, C, D, G, U, and CRF01_AE were found. All 100 sequences had mutations reported to be involved in some drug resistance, revealing naturally occurring subtype-specific amino acid patterns. Such patterns may be important to consider when treating patients infected with nonsubtype B viruses. While many drug resistance mutations seem to be naturally occurring, 9% of the newly detected patients in Sweden may have been infected with virus from antiviral-treated patients. Among the individuals infected with resistant virus, the majority were infected with subtype B virus and belonged to the homosexual risk group. It may be important to routinely test for resistance in newly infected cases to improve the choice of drugs for treatment because the virus may revert and resistant forms can become latent.