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HIV entry inhibitors, such as maraviroc (MVC), prevent cell-free viruses from entering the cells. In clinical trials, patients who were treated with MVC often displayed viral loads that were above the limit of conventional viral load detection compared to efavirenz-based regimens. We hypothesize that viruses blocked by entry inhibitors may be redistributed to plasma, where they artificially increase viral load measurements compared to those with the use of antiretroviral drugs (ARVs) that act intracellularly. We infected PM-1 cells with CCR5-tropic HIV-1 BaL or CXCR4-tropic HIV-1 NL4-3 in the presence of inhibitory concentrations of efavirenz, raltegravir, enfuvirtide, maraviroc, and AMD3100, the latter three being entry inhibitors. Supernatant viral load, reverse transcriptase enzyme activity, and intracellular nucleic acid levels were measured at times up to 24 h postinfection. Infectivity of redistributed dual-tropic HIV-1 was assessed using TZM-bl cells. Extracellular viral load analysis revealed that entry inhibitor-treated cells had higher levels of virus in the supernatant than the cells treated with other ARVs at 8 h postinfection. By 24 h, the supernatant viral load was still higher for entry inhibitors than other ARVs. We observed a correlation between viral load and the step of entry inhibition. Dual-tropic virus infectivity was undiminished utilizing the CCR5 coreceptor following redistribution by CXCR4 entry inhibition. This in vitro model indicates that entry inhibitors exhibit a redistribution effect unseen with intracellular ARV drugs. Based on these results, the effectiveness of some entry inhibitors may be underestimated if plasma viral load is used as a sole indicator of clinical success.

Background: The introduction of C-C chemokine receptor type-5 (CCR5) antagonists as antiretroviral therapy has led to the need to study HIV co-receptor tropism in different HIV-1 subtypes and geographical locations. This study was undertaken to evaluate HIV-1 co-receptor tropism in the developing world where non-B subtypes predominate, in order to assess the therapeutic and prophylactic potential of CCR5 antagonists in these regions., Methods: HIV-1-infected patients were recruited into this prospective, cross-sectional, epidemiologic study from HIV clinics in South Africa, Uganda and India. Patients were infected with subtypes C (South Africa, India) or A or D (Uganda). HIV-1 subtype and co-receptor tropism were determined and analyzed with disease characteristics, including viral load and CD4(+) and CD8(+) T cell counts., Results: CCR5-tropic (R5) HIV-1 was detected in 96% of treatment-naïve (TN) and treatment-experienced (TE) patients in India, 71% of TE South African patients, and 86% (subtype A/A1) and 71% (subtype D) of TN and TE Ugandan patients. Dual/mixed-tropic HIV-1 was found in 4% of Indian, 25% of South African and 13% (subtype A/A1) and 29% (subtype D) of Ugandan patients. Prior antiretroviral treatment was associated with decreased R5 tropism; however, this decrease was less in subtype C from India (TE: 94%, TN: 97%) than in subtypes A (TE: 59%; TN: 91%) and D (TE: 30%; TN: 79%). R5 virus infection in all three subtypes correlated with higher CD4(+) count., Conclusions: R5 HIV-1 was predominant in TN individuals with HIV-1 subtypes C, A, and D and TE individuals with subtypes C and A. Higher CD4(+) count correlated with R5 prevalence, while treatment experience was associated with increased non-R5 infection in all subtypes.

Objectives: The aim of this study was to compare the effects of an infant formula fortified with nucleotides (NF) with those of a control formula (CF) on the incidence of diarrhea, respiratory tract infections (RTIs), and immune responses in healthy term infants., Methods: This 12-month, double-blind study was conducted on 1- to 7-day-old infants randomized to receive NF or CF exclusively until 12 weeks of age, and fed the assigned formula with solid food until 12 months. NF was supplemented with 72 mg/L of nucleotides, based on the total potentially available nucleotide content of human milk. Subjects were evaluated within 1 week of birth, at 4 weeks, and every 4 weeks thereafter until 48 weeks of age. The primary outcome variable was the incidence of diarrhea. Secondary variables included RTIs, serum immunoglobulin concentrations, and response to hepatitis B vaccine., Results: Compared with subjects fed CF (n = 170), those fed NF (n = 166) had a trend toward reduced risk of diarrhea from 8 to 48 weeks of age and a significantly lower risk of 25.4% (P = 0.05) between 8 and 28 weeks. NF subjects had significantly higher serum immunoglobulin A concentrations ( P < 0.05) throughout the 48-week study. The NF group had an increased risk of upper RTIs, the same incidence of lower RTIs, and the same antibody response to hepatitis B vaccination as the CF group, based on one-sided tests. Growth was normal in both groups, and no adverse events were considered to be formula-related., Conclusions: Healthy term infants from 8 to 28 weeks of life are less likely to experience diarrhea and have higher serum immunoglobulin A concentrations with NF compared with formula without added nucleotides.