HIV envelope may hold clues to likely treatment response

Keith Alcorn
Published: 12 March 2004

Researchers at the British Columbia Centre for Excellence in HIV/AIDS may have discovered a cheap way of identifying those at higher risk of treatment failure and death despite an apparently promising early response to highly active antiretroviral therapy (HAART). Their findings, published in the journal AIDS, suggest the potential for development of a cheap and simple test that could help determine whether more intensive therapy is needed in some patients.

The group looked at blood samples from 1191 HIV-positive adults who began HAART between 1996 and 1999 in British Columbia, a Canadian province that has maintained a comprehensive database on all aspects of its HIV-positive population’s health and treatment.

Analysis focused on the relationship between a mutation in HIV's envelope within the V3 loop region, viral phenotype, CD4 decline and survival.

HIV-1 comes in two forms, or phenotypes: non-syncitium inducing (NSI) and syncitium inducing (SI). SI virus is associated with more rapid CD4 cell decline, partially through its tendency to induce the formation of syncitia, large clumps of uninfected CD4 cells that die.

SI virus is also more harmful because it is able to exploit a receptor on CD4 cells called CXCR4 to gain entry to those cells. This receptor is displayed by CD4 cells of the TH-2 type. When TH-2 CD4 cells become infected with HIV they produce much greater quantities of virus than the TH-1 cells infected by NSI virus (which favours the CCR5 receptor).

These two mechanisms explain why an SI viral phenotype is not desirable. Up until now, there has been no clear evidence that an SI phenotype was associated with a poorer response to treatment, or that a simple test that does not require painstaking viral culture would predict the presence of an SI phenotype.

The researchers looked for evidence of positively charged amino acid residues at codons 11 and 25 of HIV’s V3 loop using a genotyping method already employed in HIV resistance testing. This region on the coat of the virus has been associated with SI virus and CXCR4-utilising variants by other research groups.

V3 genotypes could be established for 91.1% of patients in the cohort, with testing conducted on stored baseline samples drawn before individuals began HAART.

Those with a positive V3 genotype (positive residues at one or both of codons 11 and 25) had a significantly increased risk of non-accidental death (RR 1.70, CI 1.06-2.71, p=0.027) after controlling for age, viral load, CD4 count, AIDS diagnosis and proportion of time on treatment in the first year after starting HAART.

Although V3 genotype did not influence the time it took for an individual to achieve a viral load below 500 copies/ml, censoring of data from patients who switched treatment before achieving viral suppression from the time of switch did show an association between positive V3 genotype and increased time to viral suppression, suggesting that those with the positive genotype may have required more intensive therapy to achieve virological control.

No association was found between V3 genotype and time to viral rebound after achieving viral load below 500 copies/ml or development of drug resistance, but a positive V3 genotype was associated with a shorter time to a CD4 decline below baseline and individuals with a positive V3 genotype had an average CD4 cell count throughout the study almost 100 cells/mm3 below the V3 negative group, suggesting that such a test might also predict which patients would benefit from immune-based therapy alongside HAART.

The authors conclude: “The relative ease and lower costs of genotyping (when compared to phenotyping assays) may make this test of practical clinical relevance in the management of HIV-infected individuals. Baseline V3 loop sequence data may provide additional information regarding therapy response and could potentially be incorporated into standard clinical genotyping procedures.”

Reference

Brumme ZL et al. Clinical and immunological impact of HIV enevelope V3 sequence variation after starting initial triple antiretroviral therapy. AIDS 18: F1-F9, 2004.

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