No evidence of ongoing HIV replication or compartmentalization in tissues during combination antiretroviral therapy: Implications for HIV eradication.

HIV persistence during combination antiretroviral therapy (cART) is the principal obstacle to cure. Mechanisms responsible for persistence remain uncertain; infections may be maintained by persistence and clonal expansion of infected cells or by ongoing replication in anatomic locations with poor antiretroviral penetration. These mechanisms require different strategies for eradication, and determining their contributions to HIV persistence is essential. We used phylogenetic approaches to investigate, at the DNA level, HIV populations in blood, lymphoid, and other infected tissues obtained at colonoscopy or autopsy in individuals who were on cART for 8 to 16 years. We found no evidence of ongoing replication or compartmentalization of HIV; we did detect clonal expansion of infected cells that were present before cART. Long-term persistence, and not ongoing replication, is primarily responsible for maintaining HIV. HIV-infected cells present when cART is initiated represent the only identifiable source of persistence and is the appropriate focus for eradication.

A20/TNFAIP3 inhibits NF-κB activation induced by the Kaposi's sarcoma-associated herpesvirus vFLIP oncoprotein.

Kaposi's sarcoma-associated herpesvirus (KSHV) K13/vFLIP (viral Flice-inhibitory protein) induces transcription of numerous genes through NF-κB activation, including pro-inflammatory cytokines, which contribute to the pathogenesis of Kaposi's sarcoma (KS). In this study, we report that KSHV vFLIP induces the expression of the NF-κB regulatory proteins A20, ABIN-1 and ABIN-3 (A20-binding NF-κB inhibitors) in primary human endothelial cells, and that KS spindle cells express A20 in KS tissue. In reporter assays, A20 strongly impaired vFLIP-induced NF-κB activation in 293T cells, but ABIN-1 and ABIN-3 did not. Mutational analysis established that the C-terminal domain (residues 427-790) is critical for A20 modulation of NF-κB, but the ubiquitin-editing OTU (ovarian tumor) domain is not. In functional assays, A20 inhibited vFLIP-induced expression of the chemokine IP-10, reduced vFLIP-induced cell proliferation and increased IKK1 protein levels. Thus, we demonstrate that A20 negatively regulates NF-κB activation directly induced by KSHV vFLIP. By attenuating excessive and prolonged vFLIP-induced NF-κB activation that could be harmful to KSHV-infected cells, A20 likely has an important role in the pathogenesis of KSHV-associated diseases, in which vFLIP is expressed.

An evaluation of the early effects of a combination antiretroviral therapy programme on the management of AIDS-associated Kaposi's sarcoma in KwaZulu-Natal, South Africa.

Roll-out of combination antiretroviral therapy (cART) in South Africa should impact on AIDS-associated Kaposi's sarcoma (KS). Government provision began in 2003, with 23% coverage for World Health Organization (WHO) stage IV AIDS in 2006. To assess the effect of cART availability on KS management, we evaluated records from 701 KS patients seen at a tertiary oncology centre in KwaZulu-Natal, South Africa, from 1995 to 2006. Associations between cART use and measures of KS care were evaluated. cART availability was 0% prior to 2001, 9.6% (2001-2003) and 44% (2004-2006). Documentation of HIV status increased incrementally from 65% to 92%. cART was associated with chemotherapy administration: 56% on cART versus 17% not on cART (P < 0.001); and less loss to follow-up, 13% on cART versus 38% not on cART (P < 0.001). cART availability improves the care of AIDS-associated KS. Further increases in cART availability for this population are needed in South Africa.

Increasing incidence of Kaposi's sarcoma in black South Africans in KwaZulu-Natal, South Africa (1983-2006).

The aim of the study was to describe the temporal trends in the incidence of Kaposi's sarcoma (KS) in black South Africans in KwaZulu-Natal (KZN). The study was designed as a retrospective record review. The incidence of Kaposi's sarcoma was estimated using administrative records for patients receiving care for KS through public sector oncology clinics in KZN, 1983-2006. Annual age-standardized incidence rates were calculated using provincial census data for the denominator. Age-specific rates were calculated for the pre-AIDS (1983-1989) and for the generalized AIDS epidemic eras (2006). Age-standardized incidence of KS increased in KZN from <1:100,000 in 1990 to at least 15:100,000 in 2006; this increase was observed in both men and women. There was a shift in the peak age-specific incidence rates from the sixth decade of life in the pre-AIDS era to the fourth and fifth decades in the AIDS era. In conclusion, KS is a growing public health problem in KZN, South Africa. These data reinforce the need for comprehensive national access to and roll-out of antiretroviral drugs, given their success in prevention and treatment of KS in first-world settings.

Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a multisystemic autosomal recessive disease due to primary thymidine phosphorylase (TP) deficiency. To restore TP activity, we performed reduced intensity allogeneic stem cell transplantations (alloSCTs) in two patients. In the first, alloSCT failed to engraft, but the second achieved mixed donor chimerism, which partially restored buffy coat TP activity and lowered plasma nucleosides. Thus, alloSCT can correct biochemical abnormalities in the blood of patients with MNGIE, but clinical efficacy remains unproven.