Elite control of a virus that caused AIDS in the transmitting partner

HIV Treat Bull - 2008 July-August;9(7/8):

A selection of articles relating to basic science and vaccine research from Richard Jeffreys excellent basic science blog.

From the online first section of J. Virology, a new paper from Justin Bailey and colleagues provides evidence that a virus that is clearly pathogenic in one individual can be controlled in another. The paper describes a couple in which the male partner received an AIDS diagnosis 10 years ago after developing PCP and cerebral toxoplasmosis; he started antiretroviral treatment and recovered with a first documented CD4 count of 266 cells. The female partner tested HIV-positive at the same time, and had no other risk factors. She has since consistently maintained CD4 counts over 800 and a viral load of less than 50 copies/mL.

Bailey and colleagues cultured several HIV isolates from the latent CD4 reservoir of both individuals, conducted full length genetic sequencing and found that the viruses are closely phylogenetically related and also contain a mutation in the tat gene that is present in less than 1% of the clade B isolates in the Los Alamos HIV sequence database. These data offer extremely strong evidence of transmission even though, as the authors note, the samples were taken many years after transmission likely occurred (the couple had been together for 17 years prior to the AIDS diagnosis). Both individuals possess the HLA B*57 allele that has been associated with elite controller status; the female partner also has another allele, HLA B*27, that has been shown to be overrepresented among elite controllers.

Additional analyses of viral sequences revealed that there were escape mutations in HLA B*57-restricted CD8 T cell epitopes in both partners. In the female partner, these mutations were present in every proviral gag clone studied, a phenomenon not observed by these authors in their larger cohort of elite controllers, suggesting that she was infected with a virus already containing the escape mutations. The authors speculate that the infecting virus may have been somewhat attenuated as a result, and subsequently the CD8 T cell response suppressed HIV replication sufficiently to prevent the development of compensatory mutations which can restore viral fitness. They also found that this individual’s CD8 cell response had selected for another mutation in an epitope called KK10 which is known to impact viral fitness; this was associated with the presence of polyfunctional CD8 T cell responses aganst both the wild-type and mutant epitope.

In further studies of immune responses, HIV-specific CD8 T cells from the female partner were shown to be able to proliferate in response to HIV antigens while those from male partner could not. The capacity for unstimulated CD8 T cells from both partners to inhibit HIV replication in vitro was also assessed (against the HIV Ba-L isolate and a virus isolated from the male partner); again, CD8 T cells from the female partner “dramatically inhibited” the replication of both viruses whereas those from the male partner did not. The researchers looked at neutralizing antibody responses to the autologous Env protein (generated by cloning the env gene from each individual’s provirus) and found that titers were low, ranging from

In discussing their results, the study authors state: “In sum, we conclude that the immune system of ES9 is controlling viral replication by at least two different mechanisms: there is direct inhibition of viral replication by polyfunctional HIV-1-specific CD8 T cells that proliferate in response to autologous viral peptides and there is selection for and maintenance of escape mutations that have a negative impact on viral fitness. Vaccines that elicit CD8 T cells with both properties may be very effective at controlling HIV-1 replication.”

Source: TAG Basic Science Blog 21 May 2008

Reference:
Bailey JR et al. Transmission of HIV-1 from a patient who developed AIDS to an elite suppressor. JVI Accepts, published online ahead of print on 21 May 2008. http://jvi.asm.org/cgi/content/abstract/JVI.00800-08v1

2008-07-10
IB080907-21

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