Factors influencing the evolution of HIV-1

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Immunology, Microbiology, Pathology and Infectious Diseases

Sammanfattning: Due to the high replication rate and the low fidelity of the viral reverse transcriptase (RT), various mutations are introduced continuously into the gene pool of HIV-1. Together with recombination events this leads to the evolution of countless quasispecies. The genetic variability of HIV-1 allows for a rapid adaptation to a new environment and is determined by multiple factors. In this thesis we studied the evolution of HIV-1 in the three structural genes that are characteristic for all retroviruses: gag, pol and env. In the gag region the p17 matrix protein was analysed. Due to its immunogenicity and conserved nature it has been considered as a promising target for immune therapies. We studied the p17 variability and its effect on both immunogenicity and antigenicity. Our data showed that the p17 gene had an interpatient variability of about 10-20%, whereas the intrapatient variability was substantially lower. This might suggest a host dependent genetic evolution of the p17 gene. We could show that two p17 quasispecies co-existing in the same patient may represent antigenically and immunogenically distinct proteins. The subtle differences within p 17 quasispecies were enough to prime distinct Th1/Th2 subsets. Also, our data indicate that the evolution of the p17 gene is influenced by contact areas with the host HLA class I molecules. The pol gene codes for the viral enzymes RT and protease. Several drugs directed against these enzymes have been introduced. These are protease inhibitors (PI), nucleoside analogues and non-nucleoside analogues RT inhibitors (NRTI, NNRTI). Suboptimal antiretroviral therapy, allowing for the viral replication to continue, is known to select for variants with reduced sensitivity to the antiretroviral agents. Several amino acid changes associated with resistance against NRTI, NNRTI and PI have been recognised in the pol gene, but also at cleaving sites for the protease. In the RT of treatment naïve patients we could hardly find any resistance to RTI, indicating that the transmission of RT resistant strains may still be rare. When analysing the protease gene, about two thirds of the patients had one or more mutations associated with resistance to PI. However, these mutations could only be detected in eight of the 16 analysed amino acid positions. This might indicate that some of the observed protease variations appear as natural polymorphisms in untreated patients. The env gene codes for the glycoproteins gp 120 and gp41. The third hypervariable region (V3 loop) of the HIV-1 surface glycoprotein gp 120 is supposed to be important for the cell tropism and cell entry. The V3 region evades constantly the host immune responses and can be used as a marker for viral evolution. We studied the evolution of the V3 region and other viral markers both in long time carriers of HIV-1 with efficient long-term antiretroviral combination therapy and in patients who received potent antiretroviral therapy from the onset of symptomatic primary HIV-1 infection (PHI). When studying the viral dynamics in the experienced patients with long-term therapy, we observed that three antiretroviral drugs were sufficient to keep the HIV-1 RNA at undetectable levels for a period of more than two years and the proviral DNA levels had decreased. However, variations in the V3 region that we observed in some of our patients suggest that the current treatment may not be sufficient to suppress virus replication completely. In the patients with PHI we observed a similar tendency. Successfully treated, in contrast to untreated patients, had undetectable viral RNA levels, decreasing viral DNA levels and showed only a minute evolution in the V3 region. An increased evolution was observed in the time period after initiation of therapy. Our studies confirm that the evolution of HIV-1 is influenced by multiple factors. The host immune response is one of the major driving forces of the viral evolution. By variations in epitope regions HIV-1 may escape the host immune responses. Moreover, even minor variations between different HIV-1 quasispecies seem to induce different immune responses. Antiretroviral treatment can either inhibit or enhance the evolution of HIV-1. Thus, successful treatment may stop the replication and evolution of HIV-1, while incomplete treatment may select for resistant variants.

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