Randomised trial of MNrgp120 HIV-1 vaccine in symptomless HIV-1 infection.

BACKGROUND: Most individuals infected with HIV-1 show disease progression despite both cellular and humoral immune responses. We investigated whether immunisation of patients who had symptomless HIV-1 infection with an envelope subcomponent vaccine (MNrgp120) to augment immune response can slow progression of HIV-1 disease. METHODS: In a randomised, double-blind, placebo-controlled trial, carried out in university infectious disease clinics and community infectious disease practices, we enrolled 573 HIV-infected patients with CD4 counts above 600 cells/microL (0.6 x 10(9)/L). Patients received 600 micrograms vaccine or placebo by intramuscular injection monthly for 6 months then every alternate month throughout the study. The primary endpoint was the rate of decline in CD4 count; secondary endpoints were HIV-1 RNA concentrations in plasma and minor clinical events associated with HIV. Analysis was by intention to treat. FINDINGS: At baseline, the study participants had a mean CD4 count of 775 cells/microL (SD 172) and 89% of participants had detectable HIV RNA (> 200 copies/mL). These RNA-positive individuals had a median viral load of 9250 copies/mL (IQR 2670-26960). Analysis after 15 months of follow-up of the 568 subjects who had at least one CD4 count done after randomisation showed no difference between the 287 vaccine recipients and 281 placebo recipients in rate of decline of CD4 count (yearly decrease 53.8 [SE 7.6] vs 42.3 [7.6] cells/microL; ratio of mean gradients 1.27 [95% CI 0.63-2.55]) or in plasma HIV-1 RNA concentrations (p > or = 0.63). The study was designed with power to detect a vaccine-induced reduction in rate of decline in CD4 count of 60%; these results exclude with 95% confidence a reduction of 40% or more. More vaccine-treated patients than placebo recipients showed a 50% decrease in CD4 count (11 vs 5; relative risk 2.15 [95% CI 0.76-6.12], p = 0.13). The frequencies of HIV-related minor clinical events were similar in the two groups. Pain at the injection site was the only adverse event that occurred more frequently in vaccine-treated group. INTERPRETATION: Postinfection immunisation of symptom-free HIV-infected patients with MNrgp120 vaccine did not alter HIV-1 disease progression as measured by immunological, virological, and clinical endpoints over a 15-month period.

Kinetics and inhibition of reverse transcriptase from human and simian immunodeficiency viruses.

Reverse transcriptase from the simian immunodeficiency virus (SIV) was found to have kinetic behavior similar to that of enzyme from the human immunodeficiency virus (HIV). Michaelis constants for the substrates TTP and dGTP and inhibition constants for the inhibitors 3'-azido-3'-deoxythymidine 5'-triphosphate, 2',3'-dideoxythymidine 5'-triphosphate, and 2'-3'-dideoxyguanosine 5'-triphosphate were obtained for SIV reverse transcriptase and were found to be similar to the corresponding values for HIV reverse transcriptase. Thus, the interaction of SIV reverse transcriptase with nucleotide analogs appears to be indistinguishable from that of the HIV enzyme, suggesting that SIV/simian acquired immunodeficiency syndrome (SAIDS) is a potentially good model of AIDS.

In vitro and in vivo activities of phosphate derivatives of 9-(1,3-dihydroxy-2-propoxymethyl)-guanine against cytomegaloviruses.

The anti-cytomegalovirus activities of four phosphate derivatives of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) were evaluated against human, monkey and murine viruses. The 5'-mono-, 3'5'-bis(mono-), and 3',5'-cyclic monophosphate and 5'-homophosphonate forms of DHPG inhibited virus plaque formation at 1-15 microM. The cyclic phosphate and homophosphonate were more active than the other compounds against murine cytomegalovirus (MCMV) in vitro. In an in vivo MCMV infection model, DHPG homophosphonate and DHPG were equally effective at reducing mortality at greater than or equal to 10 mg/kg. The cyclic phosphate was active at 10-20 mg/kg but toxic at greater than or equal to 40 mg/kg. The phosphorylation of DHPG phosphate and DHPG phosphonate, as well as the inhibition of human cytomegalovirus DNA polymerase by their respective triphosphates, were also examined.

Activity of 9-(1,3-dihydroxy-2-propoxymethyl)guanine compared with that of acyclovir against human, monkey, and rodent cytomegaloviruses.

The activities of the purine acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) against two human and five animal strains of cytomegalovirus were compared with those of acyclovir. DHPG was significantly more active than acyclovir against all but one (mouse cytomegalovirus) of the strains tested, with 50% effective doses ranging from 5 to 13 microM, as determined by plaque reduction assays in human embryonic lung (MRC-5) and human embryonic tonsil cells. Both DHPG and acyclovir inhibited virus replication at concentrations considerably lower than those necessary to inhibit cell proliferation. In mode-of-action studies, the triphosphates of DHPG and acyclovir inhibited human cytomegalovirus DNA polymerase. DHPG phosphorylation to the active triphosphate was enhanced in infected cells; however, this enzymatic activity was unrelated to thymidine kinase. In animal studies, DHPG was slightly more effective than acyclovir in reducing mouse cytomegalovirus-induced mortality.

Intracellular metabolism and enzymatic phosphorylation of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and acyclovir in herpes simplex virus-infected and uninfected cells.

The antiherpes agent 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) is a much more potent inhibitor of herpes simplex viruses in vivo than acyclovir, yet both are equally active in vitro against these viruses. To explain this difference, studies were conducted to compare the intracellular metabolism and enzymatic phosphorylation of the two compounds. In herpes type 1 and type 2 infected cells, the levels of DHPG triphosphate were only about 2-fold greater than levels of acyclovir triphosphate at virus-inhibitory concentrations (less than or equal to microM). At concentrations greater than 2.5 microM in herpes type 1 but not in type 2 infected cells, acyclovir phosphorylation was inhibited relative to that of DHPG. When drug was removed after 6 hr from infected cells, acyclovir triphosphate rapidly degraded to acyclovir and was excreted into the culture medium. In contrast, DHPG triphosphate persisted at 60-70% of the original level for 18 hr after drug removal, and DHPG excretion from cells was very slow. This finding could be a key factor to the superior potency of DHPG in animals, despite the fact that blood levels of both compounds fall rapidly after dosing. In uninfected cells, low levels of DHPG and acyclovir triphosphates were produced at 100 microM concentrations. Phosphorylation of DHPG to mono-, di- and triphosphates by purified viral and cell enzymes was more rapid than that of acyclovir. However, acyclovir triphosphate was a much more potent inhibitor of herpes virus and cell DNA polymerases.

Limited protective effect of rough mutant antisera in murine Escherichia coli bacteremia.

Previous studies in mice have demonstrated differing immunoprophylactic activity of antisera against rough mutants of Enterobacteriaceae in the prevention of lethal gram-negative bacteremia. In this study, in which CF1 mice were made bacteremic with a serum-resistant Escherichia coli 06:K2:H1, the composite survival was significantly (p less than 0.001) enhanced by i. v. pre-treatment one to two hours before injection with either normal rabbit sera or antisera to the J5 mutant of E. coli 0111. The protective efficacy of these preimmune and hyperimmune sera did not differ significantly. Since considerable variability in the mortality of control mice occurred in the 25 separate experiments, the results of individual experiments were grouped retrospectively according to survival in the individual control groups and compared for evidence of possible differences in the efficacy of these two sera. With the exception of a statistically significant difference in the efficacy in one group receiving an LD75-95 inoculum, no such differences were noted. Thus, the variable effects of a rough mutant antiserum were not explained by differences in the relative virulence in the inoculum. This study confirms earlier observations by others that the protective efficacy of the anti-J5 antisera in infected mice does not differ appreciably from that of normal rabbit sera, provided the same donor rabbits are the source of both preimmune and hyperimmune sera.