Acquired Immunodeficiency Syndrome: Brodie SJ

Berrey MM, Schacker T, Collier AC, Shea T, Brodie SJ, Mayers D, Coombs R, Krieger J, Chun TW, Fauci A, Self SG, Corey L. · Department of Medicine, University of Washington, Seattle, WA, USA. · J Infect Dis. · Pubmed #11319682 No free full text.

Abstract: Immunologic data supporting immediate antiretroviral therapy in primary human immunodeficiency virus type 1 (HIV-1) infection are emerging; however, clinical benefit has not been demonstrated. The clinical and virologic course of 47 patients who were enrolled from September 1993 through June 1996 and who were not initially treated with potent therapy was compared with the course of 20 patients who immediately began therapy with zidovudine, lamivudine, and indinavir. Demographic and baseline laboratory data were comparable. During 78 weeks of follow-up, the early-treatment cohort showed a reduced frequency of opportunistic infections (5% vs. 21.3%; relative risk, 0.11; P=.02), less frequent progression to AIDS (13% vs. 0%), and significantly less frequent nonopportunistic mucocutaneous disorders and respiratory infections (P<.01). Plasma HIV-1 RNA levels were <50 copies/mL in all patients who continued therapy; however, after 9--12 months, HIV-1 remained detectable in latently infected CD4(+) T cells and in lymph node mononuclear cells. Combination antiretroviral therapy during primary HIV-1 infection demonstrated a decreased frequency of minor opportunistic infections, mucocutaneous disorders, and respiratory infections and reduced progression to AIDS.

Brodie SJ. · University of Washington School of Medicine, Virology Division, Seattle 98195, USA. · J Leukoc Biol. · Pubmed #10985251 links to  free full text

Abstract: Autopsy tissues from 2 cohorts of age-matched HIV-infected children with similar plasma viral load (>10(5) HIV RNA copies/ml), but with distinct AIDS-associated disease manifestations, were examined for sites of persistent HIV replication. One group consisted of 3 children with severe lymphoid atrophy and peripheral blood CD4+ T cell counts of < 10/mm . Another group was composed of 6 children with extensive hyperplasia of mucosal-associated lymphoid tissues and blood CD4+ T cell counts >500/mm3. Hyperplastic bronchiole- and gut-associated lymphoid tissues were characterized by extensive networks of germinal center follicular dendritic cells (FDC) containing large amounts of immune-complexed virion RNA. Conversely, pulmonary and gastrointestinal tissues from children with severe CD4+ T cell depletion were devoid of any secondary lymphoid structures, yet these tissues also harbored high concentrations of HIV RNA. Dual in situ procedures showed that only macrophage (Mphi) within these sites contained tat fusion transcripts, a product of post-transcriptional splicing and a correlate of productive infection. When examining explant cultures of Mphi and FDC, only Mphi harbored HIV tat mRNA and only Mphi demonstrated budding retroviral particles. Hence, germinal center FDC in secondary lymphoid tissues are key reservoirs of immune-complexed HIV RNA and are likely to contribute to AIDS-associated lymphoproliferations; however, these cells do not support HIV replication, and failure to do so results from a post-transcriptional block in the virus life cycle. Moreover, gut and pulmonary Mphi represent a lineage of cells that are permissive to HIV replication and contribute significantly to the high viral load in children with severe CD4+ T cell depletion. It will be important to identify the molecular mechanisms that allow for these highly productive infections of Mphi.