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Dr Michael Seah
Clinical posts from members and guests of the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) from various international medical and scientific conferences on HIV, AIDS, viral hepatitis, and sexual health.
Promise is being shown in accessing reservoirs that cause persistence of HIV infection and finding ways to eliminate HIV in latently infected cells
HIV-1 infection and Type-1 interferon
The interaction of HIV-1 and Type-1 Interferon (IFN-1) is complex. High levels of IFN-1 during acute HIV infection results in viral suppression. Administration of IFN-1 in primary infection can result in a drop in viral load, but this effect is not seen if administered later in the disease course and there is variability in response between individuals. Continued elevation of IFN-1 in chronic HIV infection is associated with long-term immune dysfunction, including viral expansion and T cell depletion. Abstract #119
Early treatment in acute SIV Infection limits the size and distribution of the viral reservoir
Compared with starting ART at 6 weeks after infection, initiating treatment at 7 days post-infection results in a 2-log decrease in peak viral load. Initiation at 10 days results in a 1-log drop in peak viral load. Researchers also found early initiation of treatment led to improved viral control, suppression of cell associated viral RNA, and decreased levels of SIV DNA in circulating lymphocytes, suggesting a lower established reservoir of SIV in CD4 memory T cells. There was a direct correlation between peak plasma viral load and total SIV DNA in peripheral blood mononuclear cells (PBMC) at 32 weeks. Very low levels of replication competent virus were found in circulating lymphocytes of early treated animals. Viral rebound still occurs after prolonged control in these early treated animals, but there was a slower dynamic of rebound, suggesting a degree of immune mediated control. Abstract #136LB
CD4 T cell subset composition reservoirs in gut, lymph node and blood during HAART
Higher levels of HIV DNA were found in rectal mucosa, particularly in CD4 T EM cells. Peripheral blood showed a higher percentage of HIV DNA in CD4 T CM cells, and lymph nodes demonstrated a greater percentage of infected naïve CD4 T and CD4 T TM cells. Abstract #137
Proliferation of cells with HIV integrated into regulatory genes is a mechanism of persistence
HIV was found to be frequently integrated into multiple chromosomal sites, particularly into genes that control cell activation, differentiation and proliferation. The results from the study strongly suggested that the genes disrupted by HIV integration may impact cellular proliferation and survival. Proliferation of these infected cells with disrupted DNA contributes to the persistence of HIV in cellular reservoirs, particularly as the integrated HIV modifies gene function, facilitating prolonged persistence of specific infected cells. Abstract #138
"Kick and Kill"
The use of latency reversal agents (LRA) such as Histone Deacetylase inhibitors (HDACi) are being investigated to purge latently infected T cells. The theory is to reverse the latency in the infected cell, then induce an immune response to kill the cell. Researchers are finding that combinations of LRA may be required, as single agents may be insufficient to force the cell into expressing viral markers. Also, although initial administration of an LRA (Vorinostat studied in this case) may cause a transient burst in transcriptional activity, prolonged administration over 14 days results in compensatory mechanisms associated with transcriptional repression and cell survival. Abstracts #139 and #140
Cyclophosphamide (CTX) enhances SB-728-T engraftment to levels associated with HIV RNA control
CCR5 is a major co-receptor for HIV entry into cells. As found in the Berlin patient and two Boston patients, the CCR5 Δ32 mutation produces non-functional proteins where homozygotes are resistant to HIV infection and heterozygotes have slower disease progression. Researchers used CTX to enhance the engraftment of CCR5 modified autologous CD4 T cells transplanted into HIV positive subjects on ART. Subjects achieved a reduction in HIV viral load after treatment interruption, but this was not sustained. Abstract #141
Stimulation of subdominant cytotoxic lymphocyte (CTL) response is required for the elimination of HIV-1 latent reservoir
Plasma HIV-1 develops CTL escape mutations to evade the body's immune response. CD4+ T cells infected by these escape variants are insensitive to epitope-specific CTL clones, but can be killed by a broad spectrum CTL response. Research is underway to identify and stimulate subdominant CTL clones in chronically infected patients which can recognise and kill autologous target cells infected with these escape variants, and eliminate the latent viral reservoir. Abstract #142
Dendritic cell bases HIV therapeutic vaccine increases residual viraemia in individuals on ART
Vaccination with an autologous dendritic cell-HIV vaccine did not prevent viral rebound after treatment interruption and caused increased residual viraemia in 40% of subjects despite continuous ART. The vaccination may actually increase HIV-1 replication or expression from latent reservoirs. Abstract #143
HIV-1 rebound following allogenic stem cell transplantation and treatment interruption.
Two subjects underwent allogeneic hematopoietic stem cell transplantation (HSCT) from CCR5 wild-type donors, while remaining on ART. With HIV-1 remaining undetectable from blood and rectal tissue biopsy from large samples of PBMC, analytical treatment interruption (ATI) was performed. One patient had no detectable virus for 3 months and the other for 8 months before viral rebound occurred. Both patients developed symptoms of acute retroviral syndrome. Symptoms rapidly resolved with initiation of active ART with subsequent viral suppression. Researchers propose that long-lived tissue reservoirs, such as host macrophages that may be replaced more slowly than T-lymphocytes following HSCT may have contributed to viral rebound. Abstract #144LB
Impact of Systemic Cytotoxic Chemotherapy for Malignancies On HIV-1 Reservoir Persistence
HIV infected individuals undergoing cytotoxic chemotherapy for malignancies (including haemopoetic malignancies) were studied for the persistence of HIV reservoirs. Generally there was a persistence of peripheral blood reservoirs, although decreases in CD4+ T cell associated HIV-1 DNA were seen. Chemotherapy may have an impact on the viral reservoir size, but the effect depends on the type of malignancy, chemotherapy given and viral factors. Abstract #418