Robert R. Redfield

The Walter Reed Staging Classification for HTLV-III/LAV Infection

Patients with acquired immunodeficiency syndrome (AIDS) represent a minority of those who have been infected with human T-lymphotropic virus type III (HTLV-III). The clinical presentation of patients with HTLV-III infections can range from asymptomatic through chronic generalized lymphadenopathy, to subclinical and clinical T-cell deficiency. The US Army has recently adopted a staging classification for HTLV-III infection. The purpose of the Walter Reed (WR) staging Classification is to provide uniformity for routine clinical evaluation of military personnel with HTLV-III infection, to facilitate understanding of the natural history of these infections, and to help evaluate the clinical response to antiviral treatment regimens. Stage WR0 designates high-risk contacts, while stages WR1-6 require documentation of HTLV-III infection. Stages WR1-6 show ascending degrees of disease, so that those classified in WR6 manifest antibodies to HTLV-III, chronic lymphadenopathy, T helper cell counts below the normal limit, delayed hypersensitivity, thrush, and opportunistic infection. HTLV-III infections with symptoms are designated by the addition of the letter B, while the occurrence of Kaposis sarcoma is designated by adding the letter K. This classification scheme is based on the fact that the T helper cell is the principal target cell of HTLV-III and the clinical observation that the functional integrity of the T helper cell determines the clinical presentation. Preliminary studies in 39 sequential patients followed for over 18 months found that patients who entered in stages WR3-WR6 had a slow but progressive course to the next stage or death. Many questions about clinical progression remain, but it is hoped that this staging classification will facilitate their resolution.

Disseminated Vaccinia in a Military Recruit with Human Immunodeficiency Virus (HIV) Disease

LIVE-VIRUS vaccines have been well recognized as a cause of severe complications when inadvertently administered to recipients with impaired immunologic function.1 The acquired immunodeficiency syn...

A Phase I Evaluation of the Safety and Immunogenicity of Vaccination with Recombinant gp160 in Patients with Early Human Immunodeficiency Virus Infection

BACKGROUND Despite multiple antiviral humoral and cellular immune responses, infection with the human immunodeficiency virus (HIV) results in a progressively debilitating disease. We hypothesized that a more effective immune response could be generated by post-infection vaccination with HIV-specific antigens. METHODS We performed a phase I trial of the safety and immunogenicity of a vaccine prepared from molecularly cloned envelope protein, gp160, in 30 volunteer subjects with HIV infection in Walter Reed stage 1 or 2. The vaccine was administered either on days 0, 30, and 120 or on days 0, 30, 60, 120, 150, and 180. HIV-specific humoral and cellular immune responses were measured; local and systemic reactions to vaccination, including general measures of immune function, were monitored. RESULTS In 19 of the 30 subjects both humoral and cellular immunity to HIV envelope proteins increased in response to vaccination with gp160. Seroconversion to selected envelope epitopes was observed, as were new T-cell proliferative responses to gp160. Response was associated with the CD4 cell count determined before vaccination (13 of 16 subjects [81 percent] with greater than 600 cells per milliliter responded, as compared with 6 of 14 [43 percent] with less than or equal to 600 cells per milliliter; P = 0.07) and with the number of injections administered (87 percent of subjects randomly assigned to receive six injections responded, as compared with 40 percent of those assigned to three injections; P = 0.02). Local reactions at the site of injection were mild. There were no adverse systemic reactions, including diminution of general in vitro or in vivo cellular immune function. After 10 months of follow-up, the mean CD4 count had not decreased in the 19 subjects who responded, but it had decreased by 7.3 percent in the 11 who did not respond. CONCLUSIONS This gp160 vaccine is safe and immunogenic in volunteer patients with early HIV infection. Although it is too early to know whether this approach will be clinically useful, further scientific and therapeutic evaluation of HIV-specific vaccine therapy is warranted. Similar vaccines may prove to be effective for other chronic infections.

Measurement of the False Positive Rate in a Screening Program for Human Immunodeficiency Virus Infections

In a program screening civilian applicants for U.S. military service for human immunodeficiency virus (HIV) infection, we studied the frequency of false positive diagnoses retrospectively among applicants seropositive for HIV in a subpopulation with a very low prevalence of infection. That subpopulation was defined as consisting of all applicants tested between October 16, 1985, and June 30, 1987, who were young (17 or 18 years of age) and resided in a rural county in a state with a low incidence of reported acquired immunodeficiency syndrome (n = 135,187). Serum specimens from 15 applicants positive for HIV in this low-prevalence subpopulation were retrieved from a serum bank and retested by two Western blot methods, radioimmunoprecipitation, and an immunoassay constructed from a molecularly cloned and expressed viral envelope polypeptide. Fourteen of the 15 samples were unequivocally positive on all retest assays, and 1 was negative. Thus, the measured rate of false positive diagnoses in this program was 1 in 135,187 persons tested. Factors important in achieving a low false positive rate were redundant, multistep testing algorithm, conservative criteria for interpreting Western blots, the requirement that a second, newly drawn serum specimen be tested for verification before a diagnosis of HIV was considered established, and tight quality control of laboratory testing procedures. We conclude that a screening program for HIV infection in a low-prevalence population can have an acceptably low false positive rate.

Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, have profound and synergistic anti-HIV activity.

The use of inhibitors of purine nucleoside metabolism has been advocated for the treatment of HIV-1 infection. Abacavir is the first clinically available guanosine analogue HIV-1 reverse transcriptase inhibitor, and the most potent nucleoside analogue yet developed. Mycophenolic acid (MA), a specific inhibitor of lymphocyte proliferation that is currently in use in organ transplantation, acts on inosine monophosphate dehydrogenase to block conversion of inosine monophosphate to guanosine monophosphate. We found abacavir and MA inhibited HIV-1 replication in stimulated peripheral blood mononuclear cells (PBMCs) and in monocyte-derived macrophages (MDMs). Inhibition was potent and synergistic to an extent not previously observed with other antiretroviral combinations. MA was effective at concentrations (0.25 microM) far below those used for immunosuppression in organ transplantation. An HIV strain encoding the M184V mutation was susceptible to the combination of MA and abacavir. However, the combination of MA and zidovudine (ZDV) or stavudine (d4T) was antagonistic. Although the translation of these observations must be carefully evaluated in clinical trials, the judicious combination of antiretrovirals and inhibitors of nucleoside metabolism may emerge as an important strategy in the treatment of HIV infection.

Human immunodeficiency virus infections among civilian applicants for United States military service, October 1985 to March 1986: Demographic factors associated with seropositivity

During the six months from October 1985 through March 1986, blood samples from 306,061 civilian applicants for military service from the United States were tested for antibody to the human immunodeficiency virus (HIV). Four hundred sixty subjects were positive for the antibody as determined by Western (immune) blot reactivity. The mean prevalence of HIV infection in this population of teenagers and young adults was thus 1.50 per 1000. According to multivariate analysis, the following demographic factors were found to be significant independent predictors of a positive HIV-antibody test: age (adjusted odds ratio = 1.10 per year), black race (adjusted odds ratio = 2.04), male sex (adjusted odds ratio = 1.84), residence in a densely populated county (adjusted odds ratio = 1.05 per 1000 per square mile), and residence in a metropolitan area with a high incidence of the acquired immunodeficiency syndrome (adjusted odds ratio = 1.53). Antibody-positive applicants were identified in 43 of the 50 states. Counties with high prevalence rates for HIV (greater than 5 per 1000) were located in New York State (four counties), New Jersey (three counties), California (two counties), Maryland (two counties), and Texas, Colorado, and Washington, D.C.

Antiviral activity of single-dose PRO 140, a CCR5 monoclonal antibody, in HIV-infected adults

BACKGROUND The current goal of human immunodeficiency virus type 1 (HIV-1) therapy is to maximally suppress viral replication. Securing this goal requires new drugs and treatment classes. The chemokine receptor CCR5 provides an entry portal for HIV-1, and PRO 140 is a humanized monoclonal antibody that binds to CCR5 and potently inhibits CCR5-tropic (R5) HIV-1 in vitro. METHODS A randomized, double-blind, placebo-controlled, dose-escalating study was conducted in 39 individuals with HIV-1 RNA levels or =5000 copies/mL, CD4(+) cell counts > or =250 cells/microL, no antiretroviral therapy for 3 months, and only R5 HIV-1 detectable. Cohorts were randomized 3:10 to receive placebo or doses of PRO 140 of 0.5, 2, or 5 mg/kg. Subjects were monitored for 58 days for safety, antiviral effects, and serum concentrations of PRO 140. RESULTS PRO 140 was generally well tolerated and demonstrated potent, rapid, prolonged, and dose-dependent antiviral activity. Mean reductions in HIV-1 RNA level of 0.58 log(10), 1.20 log(10) (P= .0002) and 1.83 log(10) (P= .0001) were observed for the 0.5-, 2-, and 5-mg/kg dose groups, respectively. Reductions in mean viral load of > or =10-fold were observed within 4 days and persisted for 2-3 weeks after treatment. CONCLUSIONS This trial established clear proof of concept for PRO 140 as a potent antiretroviral agent with extended activity after a single dose. TRIAL REGISTRATION ISRCTN Register: ISRCTN45537485 .

Evaluation of initial CD4+ T cell counts in individuals with newly diagnosed human immunodeficiency virus infection, by sex and race, in urban settings

The CD4+ T cell count is an important determinant of disease stage and prognosis in human immunodeficiency virus (HIV)-infected individuals. This study evaluated the CD4+ T cell counts in individuals at the time of diagnosis of HIV infection at 4 community clinics in large urban settings with relatively high frequencies of HIV infection. Of 2223 individuals, 57% and 36% had CD4+ T cell counts < 350 and < 200 cells/mm(3), respectively, at the time of diagnosis. There were no clear differences by sex or race. Enhanced educational efforts regarding the importance of HIV testing for at-risk individuals across sex and race strata in community settings may be important for early identification of individuals with HIV infection. This in turn could impact efforts to reduce transmission, and it could impact the prognosis for patients who receive antiretroviral therapy.

Clinical use of CCR5 inhibitors in HIV and beyond.

Since the discovery of CCR5 as a coreceptor for HIV entry, there has been interest in blockade of the receptor for treatment and prevention of HIV infection. Although several CCR5 antagonists have been evaluated in clinical trials, only maraviroc has been approved for clinical use in the treatment of HIV-infected patients. The efficacy, safety and resistance profile of CCR5 antagonists with a focus on maraviroc are reviewed here along with their usage in special and emerging clinical situations. Despite being approved for use since 2007, the optimal use of maraviroc has yet to be well-defined in HIV and potentially in other diseases. Maraviroc and other CCR5 antagonists have the potential for use in a variety of other clinical situations such as the prevention of HIV transmission, intensification of HIV treatment and prevention of rejection in organ transplantation. The use of CCR5 antagonists may be potentiated by other agents such as rapamycin which downregulate CCR5 receptors thus decreasing CCR5 density. There may even be a role for their use in combination with other entry inhibitors. However, clinical use of CCR5 antagonists may have negative consequences in diseases such as West Nile and Tick-borne encephalitis virus infections. In summary, CCR5 antagonists have great therapeutic potential in the treatment and prevention of HIV as well as future use in novel situations such as organ transplantation. Their optimal use either alone or in combination with other agents will be defined by further investigation.

synergistic Inhibition of Hiv-1 in Activated and Resting Peripheral Blood Mononuclear Cells, Monocyte-derived Macrophages, and Selected Drug-resistant Isolates With Nucleoside Analogues Combined With a Natural Product, Resveratrol

&NA;Resveratrol (trans‐3,5,4′‐trihydroxystilbene) is a phytoalexin present in grapes, wine, and certain plants, which has recently been reported to possess properties that may protect against atherosclerosis, certain cancers, and inflammation. We now report that resveratrol (RV) synergistically enhances the anti‐HIV‐1 activity of the nucleoside analogues zidovudine (AZT), zalcitabine (ddC), and didanosine (ddl). RV at 10 &mgr;M was not toxic to cells, and by itself reduced viral replication by 20% to 30%. In phytohemagglutinin (PHA)‐activated peripheral blood mononuclear cells (PBMCs) infected with HTLV‐IIIB, 10 &mgr;M RV reduced the 90 % inhibitory concentration (IC90) of AZT, ddC, and ddI by 3.5‐, 5.5‐, and 17.8‐fold, respectively. Similar antiviral activity was demonstrated when ddI was combined with 5 or 10 mM RV in PBMCs infected with clinical isolates of HIV‐1. The addition of RV resulted in a > 10‐fold augmentation of ddI‐antiviral activity in infected monocyte‐derived macrophages (MDMs). In a resting cell model of T lymphocytes which were infected with HTLV‐IIIB, RV plus ddI in combination, but not individually, suppressed establishment of a productive viral infection. In addition, RV plus ddI markedly inhibited the replication of four ddI‐resistant viral isolates, three of which presented mutations in the RT gene conferring RT‐multidrug resistance. Finally, when compared with hydroxyurea (HU), both 100 mM HU and 10 mM RV showed similar enhancement of ddI‐antiviral suppressive activity. However, RV was shown to have less of a cellular antiproliferative effect than HU.