PubMed · 10325199
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L Wagner. 1988-03-04. $20 billion AIDS program recommended.. https://pubmed.ncbi.nlm.nih.gov/10325199/
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Multiple nucleoside resistance involves specific mutational patterns of the HIV-1 pol gene that are independent of the classic mutations conferring resistance to individual dideoxynucleosides. These include a cluster of five mutations in the reverse-transcriptase (RT) coding region (A62V, V75I, F77L, F116Y, and Q151M) generally referred to as multidrug resistance (MDR) mutations, and insertions of one or several amino acid residues between codons 67 and 70 of RT, a flexible region joining two antiparrallel beta sheets (beta3-beta4 insertions). The objectives of this study were (i) to determine the prevalence of multidrug resistance genotypes (MDR mutations and beta3-beta4 insertions) in a cohort of 632 patients who were extensively pretreated with anti-HIV drugs and not responding to their current antiretroviral therapy, and (ii) to analyze the association of multidrug resistance genotypes with other resistance mutations in the RT and protease genes. Among viruses sequenced from these patients, 15 (2.4%) of them contained an insertion and 2 (0.3%) contained a deletion in the beta3-beta4 finger subdomain of RT. In 9 cases, the insertion was associated with a D67S, G, or E mutation. In addition, we identified 13 (2.1%) viruses harboring specific MDR mutations (mainly Q151M and/or A62V, V75I, F116Y). Interestingly, the A62V mutation was found in 6 of the 15 strains with an insertion, whereas the other MDR mutations were not observed in insertion mutant strains. Especially high levels of resistance to zidovudine were observed for viruses with a beta3-beta4 insertion in the background of A62V, L210W, and T215Y. Otherwise, MDR mutations and beta3-beta4 insertions were found in association with the classic mutations conferring resistance to zidovudine, lamivudine, nonnucleoside RT inhibitors, and protease inhibitors, according to treatment history. Finally, we observed a genome with a deletion of codon 70 associated with a Q151M MDR mutation. These data suggest that the emergence of HIV-1 multidrug resistance, which may occur in various genetic contexts, poses a challenging problem in formulating treatment strategies.
The influence of human T-cell leukemia/lymphoma virus type II (HTLV-II) in individuals also infected with HIV-1 is poorly understood. To evaluate the reciprocal influence of HTLV-II and HIV-1 infection, primary peripheral blood mononuclear cell (PBMC) cultures from coinfected individuals were established in the presence of interleukin 2 (IL-2). In these cultures, the kinetics of HTLV-II replication always preceded those of HIV-1. Noteworthy, the kinetics of HIV-1 production were inversely correlated to the HTLV-II proviral load in vivo and its replication ex vivo. These observations suggested a potential interaction between the 2 retroviruses. In this regard, the levels of IL-2, IL-6, and tumor necrosis factor-alpha (TNF-alpha) were measured in the same coinfected PBMC cultures. Endogenous IL-2 was not produced, whereas IL-6 and TNF-alpha were secreted at levels compatible with their known ability to up-regulate HIV-1 expression. The HIV-suppressive CC-chemokines RANTES, macrophage inflammatory protein-1alpha (MIP-1alpha), and MIP-1beta were also determined in IL-2-stimulated PBMC cultures. Of interest, their kinetics and concentrations were inversely related to those of HIV-1 replication. Experiments were performed in which CD8(+) T cells or PBMCs from HTLV-II monoinfected individuals were cocultivated with CD4(+) T cells from HIV-1 monoinfected individuals separated by a semipermeable membrane in the presence or absence of antichemokine neutralizing antibodies. The results indicate that HTLV-II can interfere with the replicative potential of HIV-1 by up-regulating viral suppressive CC-chemokines and, in particular, MIP-1alpha. This study is the first report indicating that HTLV-II can influence HIV replication, at least in vitro, via up-regulation of HIV-suppressive chemokines. (Blood. 2000;95:2760-2769)
OBJECTIVE: To examine the effect of different antiretroviral treatment regimens on viral load, CD4 lymphocyte counts, and rates of progression to clinical acquired immunodeficiency syndrome events among treatment-naive human immunodeficiency virus (HIV)-infected patients enrolled in a large community cohort study. METHODS: Based in 7 outpatient clinics, the Swiss HIV Cohort Study is a cohort with national coverage. Virological, immunologic, and clinical results of 755 treatment-naive patients (median age, 36 years; 28.2% female) who initiated antiretroviral therapy between July 1, 1995, and June 30, 1997, were analyzed. Patients started undergoing monotherapy with 1 reverse transcriptase inhibitor (RTI), combination therapy with at least 2 RTIs, or highly active antiretroviral therapy (HAART) with RTIs and protease inhibitors. RESULTS: Antiretroviral treatment led to a mean reduction of viremia of 1.8 log10 copies per milliliter with HAART, 1.2 log10 copies per milliliter with RTI combination therapy, and 0.4 log10 copies per milliliter with monotherapy. Virological failure, defined as less than 1 log10 reduction per milliliter in viremia, was present in 45 (20%) patients undergoing HAART, 180 (38%) undergoing RTI combination therapy, and 47 (82%) undergoing monotherapy. The proportion of patients reaching undetectable viremia was 12% (n = 7) for monotherapy, 41% (n = 197) for RTI combination therapy, and 63% (n = 137) for HAART. Similar gains of CD4 cells were achieved with RTI combination therapy and HAART. Kaplan-Meier estimates of progression rates to a new acquired immunodeficiency syndrome event at 18 months were 13.6% (monotherapy), 4.7% (RTI combination therapy), and 3.9% (HAART). CONCLUSIONS: The rate of virological failure of antiretroviral treatments was high in this population of treatment-naive patients, even among patients receiving combination regimens. Clinical progression rates were, however, low in patients treated with RTI combination therapy and HAART.