Despite the clinical benefits of combination antiviral therapy, whether maximal antiviral potency has been achieved with current drug combinations remains unclear. We studied the first phase of decay of human immunodeficiency virus type 1 (HIV-1) RNA in plasma, one early indicator of antiviral activity, after the administration of a novel combination of lopinavir/ritonavir, efavirenz, tenofovir disoproxil fumarate, and lamivudine and compared it with that observed in matched cohorts treated with alternative combination regimens. On the basis of these comparisons, we conclude that the relative potency of highly active antiretroviral therapy may be augmented by as much as 25%-30%. However, it is important to emphasize that further study is warranted to explore whether these early measurements of relative efficacy provide long-term virologic and clinical benefits. Nevertheless, we believe that optimal treatment regimens for HIV-1 have yet to be identified and that continued research to achieve this goal is warranted.

Louie Michael    Hogan Christine    Di Mascio Michele    Arlene Hurley    Simon Viviana    James Rooney    Ruiz Nancy    Brun Scott C.    Sun Eugene    Alan Perelson    何大一     Markowitz Martin   

Journal of Infectious Diseases

2003

Cellular turnover rates in the immune system can be determined by labelling dividing cells with 5-bromo-2′-deoxyuridine (BrdU) or deuterated glucose (H-glucose). To estimate the turnover rate from such measurements one has to fit a particular mathematical model to the data. The biological assumptions underlying various models developed for this purpose are controversial. Here, we fit a series of different models to BrdU data on CD4 T cells from SIV and SIV rhesus macaques. We first show that the parameter estimates obtained using these models depend strongly on the details of the model. To resolve this lack of generality we introduce a new parameter for each model, the 'average turnover rate', defined as the cellular death rate averaged over all subpopulations in the model. We show that very different models yield similar estimates of the average turnover rate, i.e. ca. 1% day in uninfected monkeys and ca. 2% day in SIV-infected monkeys. Thus, we show that one can use BrdU data from a possibly heterogeneous population of cells to estimate the average turnover rate of that population in a robust manner.

de Boer Rob J.    Mohri Hiroshi    何大一     Alan Perelson   

Proceedings of the Royal Society B: Biological Sciences

2003

γδ T cells are primarily found in the gastrointestinal mucosa and play an important role in the first line of defense against viral, bacterial, and fungal pathogens. We sought to examine the impact of human immunodeficiency virus type 1 (HIV-1) infection on mucosal as well as peripheral blood γδ T-cell populations. Our results demonstrate that HIV-1 infection is associated with significant expansion of Vδ1 and contraction of Vδ2 cell populations in both the mucosa and peripheral blood. Such changes were observed during acute HIV-1 infection and persisted throughout the chronic phase, without apparent reversion after treatment with highly active antiretroviral therapy (HAART). Despite an increase in the expression of CCR9 and CD103 mucosal homing receptors on peripheral blood γδ T cells in infected individuals, mucosal and peripheral blood γδ T cells appeared to be distinct populations, as reflected by distinct CDR3 length polymorphisms and sequences in the two compartments. Although the underlying mechanism responsible for triggering the expansion of Vδ1 γδ T cells remains unknown, HIV-1 infection appears to have a dramatic impact on γδ T cells, which could have important implications for HIV-1 pathogenesis.

Poles Michael    Barsoum Shady    Wenjie Yu    Yu Jian    Sun Patricia    Daly Jeanine    He T.    Mehandru    Talal    Markowitz Martin    Arlene Hurley    何大一     Zhang Linqi   

Journal of Virology

2003

The predominant mode of HIV transmission worldwide is via heterosexual contact, with the cervico-vaginal mucosa being the main portal of entry in women. The cervico-vaginal mucosa is naturally colonized with commensal bacteria, primarily lactobacilli. To address the urgent need for female-controlled approaches to block the heterosexual transmission of HIV, we have engineered natural human vaginal isolates of Lactobacillus jensenii to secrete two-domain CD4 (2D CD4) proteins. The secreted 2D CD4 recognized a conformation-dependent anti-CD4 antibody and bound HIV type 1 (HIV-1) gp120, suggesting that the expressed proteins adopted a native conformation. Single-cycle infection assays using HIV-1 carrying a luciferase reporter gene demonstrated that Lactobacillus-derived 2D CD4 inhibited HIV-1 entry into target cells in a dose-dependent manner. Importantly, coincubation of the engineered bacteria with recombinant HIV-1 reporter virus led to a significant decrease in virus infectivity of HeLa cells expressing CD4-CXCR4-CCR5. Engineered lactobacilli also caused a modest, but statistically significant, decrease in infectivity of a primary isolate, HIV-1 . This represents an important first step toward the development of engineered commensal bacteria within the vaginal microflora to inhibit heterosexual transmission of HIV.

Chang Theresa    Chang Chia Hwa    Simpson David A.    Xu Qiang    Martin Patrick K.    Lagenaur    Schoolnik Gary K.    何大一     Hillier Sharon    Holodniy Mark    Lewicki John A.    Lee Peter   

Proceedings of the National Academy of Sciences of the United States of America

2003

Although intermittent episodes of low-level viremia are often observed in well-suppressed highly active antiretroviral therapy (HAART)-treated patients, the timing and amplitude of viral blips have never been examined in detail. We analyze here the dynamics of viral blips, i.e., plasma VL measurements of >50 copies/mi, in 123 HAART-treated patients monitored for a mean of 2.6 years (range, 5 months to 5.3 years). The mean (± the standard deviation) blip frequency was 0.09 ± 0.11/sample, with about one-third of patients showing no viral blips. The mean viral blip amplitude was 158 ± 132 human immunodeficiency virus type 1 (HIV-1) RNA copies/mi. Analysis of the blip frequency and amplitude distributions suggest that two blips less than 22 days apart have a significant chance of being part of the same episode of viremia. The data are consistent with a hypothetical model in which each episode of viremia consists of a phase of VL rise, followed by two-phase exponential decay. Thus, the term "viral blip" may be a misnomer, since viral replication appears to be occurring over an extended period. Neither the frequency nor the amplitude of viral blips increases with longer periods of observation, but the frequency is inversely correlated with the CD4 -T-cell count at the start of therapy, suggesting that host-specific factors but not treatment fatigue are determinants of blip frequency.

Di Mascio Michele    Markowitz Martin    Louie Michael    Hogan Christine    Arlene Hurley    Chung Christopher W.    何大一     Alan Perelson   

Journal of Virology

2003

The advent of potent combination antiretroviral therapy has been an important breakthrough in the treatment of HIV-1 infection, resulting in marked reductions in HIV-1-related morbidity and mortality. Antiretroviral therapy has also provided researchers with a powerful tool to perturb the equilibrium of viral production and viral clearance, allowing them to dissect the underlying dynamics that control the pathogenesis of AIDS. Here, we review our current understanding of the sources of HIV-1 production, the estimates for the virion and the host-cell half-lives, and the pathways of virion trafficking and clearance. We also discuss the obstacles that result from the ability of HIV-1 to remain dormant for a prolonged period of time in a subset of long-lived cells, despite an apparently effective antiretroviral treatment. © 2003, Nature Publishing Group. All rights reserved.

Simon Viviana    何大一    

Nature Reviews Microbiology

2003

In order to boost immune responses in persons in whom highly active antiretroviral therapy (HAART) was initiated within 120 days of the onset of symptoms of newly acquired human immunodeficiency virus type 1 (HIV-1) infection, we administered vaccines containing a canarypox virus vector, vCP1452, with HIV-1 genes encoding multiple HIV-1 proteins, and recombinant gp160. Fifteen HIV-1-infected subjects who achieved sustained suppression of plasma viremia for at least 2 years were enrolled. While continuing antiretroviral therapy, each subject received at least four intramuscular injections of the vaccines on days 0, 30, 90, and 180. Adverse events were mild, with the most common being transient tenderness at the vCP1452 injection site. Of the 14 patients who completed vaccination, 13 had significant increases in anti-gp120 or anti-p24 antibody titers, and 9 had transient augmentation of their T-cell proliferation responses to gp160 and/or p24. HIV-1-specific CD8 T cells were quantified using an intracellular gamma interferon staining assay. Among 11 patients who had increased CD8 T-cell responses, seven had responses to more than one HIV-1 antigen. In summary, vaccination with vCP1452 and recombinant gp160 appears safe and immunogenic in newly HIV-1-infected patients on HAART.

金侠    Ramanathan Murugappan    Barsoum Shady    Deschenes Geoffrey R.    Ba Lei    Binley James M.    Schiller Daryl    Daniel Bauer    Chen Donald C.    Arlene Hurley    Gebuhrer    El Habib Raphaëlle    Caudrelier Pierre    Klein Michel    Zhang Linqi    何大一     Markowitz Martin   

Journal of Virology

2002

Infection with human or simian immunodeficiency virus (SIV) is characterized by the rapid turnover of both viral particles and productively infected cells. It has recently been reported that the clearance of SIV in vivo is exceedingly fast, with half-lives on the order of minutes. The underlying mechanism or site responsible for this rapid clearance, however, remains unknown. To investigate this issue, we chose to infuse infectious SIVmac239 grown from autologous peripheral blood mononuclear cells that were radioactively labeled by [S] methionine and [S] cysteine. This approach eliminates from the viral membrane alloantigens that may have a significant impact on viral clearance. In addition, this approach also permits identification of the sites of viral clearance by measuring the radioactive intensity, even if degradation of SIV RNA occurs in tissues. We now report that the half-life of infused SIV in blood is extremely close to estimates from a previous study, in which unlabeled SIV grown in a heterologous cell line was used. The allogeneic effect due to the presence of human antigens on the surfaces of virions may, therefore, play a minimal role in the high rate of virion clearance. Moreover, close to 30% of infused radioactivity was found in the liver and measurable amounts were detected in the lungs (5.4%), lymph nodes (3.0%), and spleen (0.4%). The detection of a significant proportion of infused virus in the liver suggests that viral clearance from circulation is mediated by a common, nonspecific mechanism, such as the phagocytic functions of the reticuloendothelial system. The rapid clearance and degradation of exogenously infused virions may pose a major obstacle for gene therapy with viral vectors, unless strategies to overcome the rapid in vivo elimination of these particles are developed.

Zhang Linqi    Dailey Peter    Gettie Agegnehu    Blanchard James    何大一    

Journal of Virology

2002

We investigated the dynamics of lymphocyte turnover in normal subjects as well as in HIV-1-infected patients using a novel labeling technique based on the administration of deuterium-containing glucose. A new mathematical model was also used to interpret the results. This approach provided direct determination of lymphocyte proliferation and death rates. We believe our findings convincingly demonstrate the increased turnover (3-6 fold) of both CD4 and CD8 lymphocytes in HIV-1 infection. Furthermore, we also noted that the heightened T-cell turnover reverted toward normal upon effective combination antiretroviral therapy. Collectively, these data show that the lymphocyte depletion seen in AIDS is not a consequence of a T-cell regenerative failure. We have also assessed the role of thymus in contributing to T-lymphocyte homeostasis with and without SIV infection. Upon thymectomy in rhesus macaques, we noted a very gradual decline in the number of recent thymic emigrants as measured by the number of T-cell receptor excision circles. These results suggest that the normal thymic output in monkeys is small, and that recent thymic emigrants typically have a prolonged lifespan. We have also found relatively little impact of thymectomy on the outcome of SIV infection. Again, these findings indicate that thymus does not play a major role in the lymphocyte depletion observed in SIV or HIV infection.

何大一    

Proceedings of the Annual International Conference on Computational Molecular Biology, RECOMB

2002

Human immunodeficiency virus type 1 (HIV-1) infects cells of the immune system and leads to depletion of CD4 T cells, and to an increase of CD8 T-lymphocytes. However, not much is known about the dynamics of turnover (proliferation and death) of the CD4 and CD8 T cell populations in HIV-infected and healthy individuals. A new experimental technique has been developed using deuterated- glucose labeling that provides information on cell turnover in vivo. However, the quantitative interpretation of the data requires the development of specific dynamic models. In this paper we derive two models, a simple one-compartment model and a more complex two-compartment model. These models allow for robust quantification of death and proliferation rates, but careful consideration of the system is necessary to understand what is being measured in each case. We demonstrate that more realistic models can account not only for differences in the turnover rates between HIV-infected and healthy individuals, but also take into consideration the elevated state of activation in HIV infection. The use of these models in the interpretation of the experimental data will increase our knowledge of T cell dynamics in the context of HIV infection. © 2002 Society for Mathematical Biology.

Ruy Ribeiro    Mohri Hiroshi    何大一     Alan Perelson   

Bulletin of Mathematical Biology

2002