HIV and lymphocyte dynamics.
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Journal Article↗
Biomedical subjects
David D Ho
Publications and source records attributed to David D Ho.
Modeling deuterated glucose labeling of T-lymphocytes.
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.
CD4-Positive T-Lymphocytes↗
The liver is a major organ for clearing simian immunodeficiency virus in rhesus monkeys.
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 [(35)S]methionine and [(35)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 measureable 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.
Animals↗
Compartmentalization of surface envelope glycoprotein of human immunodeficiency virus type 1 during acute and chronic infection.
Human immunodeficiency virus type 1 is characterized by extensive genetic heterogeneity. Having previously demonstrated that, in the peripheral blood, the initial viral population is more homogeneous than at subsequent stages of infection, we have extended our studies to tissue samples, allowing comparisons between viral populations in peripheral blood and tissues during both the acute and chronic stages of infection. We found that homogeneity in gp120 sequences during the acute infection phase is not just restricted to the peripheral blood but also extends to other tissue compartments. However, in chronically infected individuals, heterogeneous and distinct viral populations were found in different compartments. We therefore conclude that the dominant and homogeneous viral population observed during the acute infection phase is likely to infiltrate lymphoid tissues and form the genetic bases for subsequent diversification. It is therefore likely that the compartmentalization of viral sequences observed in chronically infected patients reflects a gradual diversification of a common dominant viral variant rather than the preferential migration of distinct viral populations to different tissue compartments at the beginning of infection.
Acute Disease↗
Human immunodeficiency virus type 1 (HIV-1)-specific CD8+-T-cell responses for groups of HIV-1-infected individuals with different HLA-B*35 genotypes.
Human immunodeficiency virus type 1 (HIV-1)-infected individuals with HLA-B*35 allelic variants B*3502/3503/3504/5301 (B*35-Px) progress more rapidly to AIDS than do those with B*3501 (B*35-PY). The mechanisms responsible for this phenomenon are not clear. To examine whether cellular immune responses may differ according to HLA-B*35 genotype, we quantified HIV-1-specific CD8(+)-T-cell (CTL) responses using an intracellular cytokine-staining assay with specimens from 32 HIV-1-positive individuals who have B*35 alleles. Among them, 75% had CTL responses to Pol, 69% had CTL responses to Gag, 50% had CTL responses to Nef, and 41% had CTL responses to Env. The overall magnitude of CTL responses did not differ between patients bearing B*35-Px genotypes and those bearing B*35-PY genotypes. A higher percentage of Gag-specific CTL was associated with lower HIV-1 RNA levels (P = 0.009) in individuals with B*35-PY. A negative association between CTL activity for each of the four HIV antigens and viral load was observed among individuals with B*35-PY, and the association reached significance for Gag. No significant relationship between CTL activity and viral load was observed in the B*35-Px group. The relationship between total CTL activity and HIV RNA among B*35-Px carriers differed significantly from that among B*35-PY carriers (P < 0.05). The data are consistent with the hypothesis that higher levels of virus-specific CTL contribute to protection against HIV disease progression in infected individuals with B*35-PY, but not in those with B*35-Px.
Acquired Immunodeficiency Syndrome↗
Safety and immunogenicity of ALVAC vCP1452 and recombinant gp160 in newly human immunodeficiency virus type 1-infected patients treated with prolonged highly active antiretroviral therapy.
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.
AIDS Vaccines↗
Modeling the long-term control of viremia in HIV-1 infected patients treated with antiretroviral therapy.
Highly active antiretroviral therapy (HAART), administered to a HAART-naïve patient, perturbs the steady state of chronic infection. This perturbation provides an opportunity to investigate the existence and dynamics of different sources of viral production. Models of HIV dynamics can be used to make a comparative analysis of the efficacies of different drug regimens. When HAART is administered for long periods of time, most patients achieve 'undetectable' viral loads (VLs), i.e., below 50 copies/ml. Use of an ultrasensitive VL assay demonstrates that some of these patients obtain a low steady state VL in the range 5-50 copies/ml, while others continue to exhibit VL declines to below 5 copies/ml. Interestingly, when patients exhibit continued declines below 50 copies/ml the virus has a half-life of approximately 6 months, consistent with some estimates of the rate of latent cell decline. Some patients, despite having sustained undetectable VLs, show periods of transient viremia (blips). We present a statistical characterization of the blips observed in a set of 123 patients, suggesting that patients have different tendencies to show blips during the period of VL suppression, that intermittent episodes of viremia have common amplitude profiles, and that VL decay from the peak of a blip may have two phases.
Antiretroviral Therapy, Highly Active↗
Infection with multidrug resistant, dual-tropic HIV-1 and rapid progression to AIDS: a case report.
BACKGROUND: Rapid progression to AIDS after acute HIV-1 infection, though uncommon, has been noted, as has the transmission of multidrug resistant viruses. Here, we describe a patient in whom these two factors arose concomitantly and assess the effects. METHODS: We did a case study of a patient with HIV-1 seroconversion. We genotyped the virus and host genetic markers by PCR and nucleotide sequencing. To ascertain the drug susceptibility of our patient's HIV-1 we did phenotypic studies with the PhenoSense assay. We assessed viral coreceptor use via syncytium formation in vitro and with a modified PhenoSense assay. FINDINGS: Our patient seems to have been recently infected by a viral variant of HIV-1 resistant to multiple classes of antiretroviral drugs. Furthermore, his virus population is dual tropic for cells that express CCR5 or CXCR4 coreceptor. The infection has resulted in progression to symptomatic AIDS in 4-20 months. INTERPRETATION: The intersection of multidrug resistance and rapid development of AIDS in this patient is of concern, especially in view of his case history, which includes high-risk sexual contacts and use of metamfetamine. The public health ramifications of such a case are great.
Acquired Immunodeficiency Syndrome↗