What does the structure-function relationship of the HIV-1 Tat protein teach us about developing an AIDS vaccine?

The human immunodeficiency virus type 1 (HIV-1) trans-activator of transcription protein Tat is an important factor in viral pathogenesis. In addition to its function as the key trans-activator of viral transcription, Tat is also secreted by the infected cell and taken up by neighboring cells where it has an effect both on infected and uninfected cells. In this review we will focus on the relationship between the structure of the Tat protein and its function as a secreted factor. To this end we will summarize some of the exogenous functions of Tat that have been implicated in HIV-1 pathogenesis and the impact of structural variations and viral subtype variants of Tat on those functions. Finally, since in some patients the presence of Tat-specific antibodies or CTL frequencies are associated with slow or non-progression to AIDS, we will also discuss the role of Tat as a potential vaccine candidate, the advances made in this field, and the importance of using a Tat protein capable of eliciting a protective or therapeutic immune response to viral challenge

Infection of a simian B cell line by human and simian immunodeficiency viruses

It is well known that HIV-1 does not establish infection in nonhuman primates, nor in cell lines derived from them, due to the existence of saturable resistance factors. In this study, we show that an in vitro established Macaca fascicularis-derived CD4(-) B cell line (F6) can be productively infected by the laboratory-adapted T-tropic HXBc2/HIV-1 strain at low multiplicity of infection, apparently because it does not express the restriction factor that has been detected in other simian cell lines. Moreover, efficient entry into F6 cells was obtained with pseudotyped recombinant HIV-1 viruses containing the laboratory-adapted T-tropic (HXBc2) or the dual-tropic (89.6) envelope glycoproteins, whereas entry of virus containing the envelope glycoproteins of the M-tropic Ba-L strain was less efficient. Virus containing primary T-tropic (Eli) envelope glycoproteins did not infect F6 cells. Furthermore, although CCR5 was not present on the cell surface and gpr15 and strl33 mRNAs were not expressed in the cells, a high level of infection of F6 cells by the M-tropic simian immunodeficiency virus SIVmac316 was observed. In contrast, F6 cells were poorly infected by T-tropic SIVmac239. Given the unique properties of the F6 cell line, i.e., that it is of simian origin yet is able to be infected by HIV-1 in a CD4-independent manner, F6 cells represent a useful model for studying cellular factors mediating resistance or permissivity to HIV-1 infection and may help to evaluate HIV-1 and SIV cell tropism

Characterization of HIV-1 Subtypes among South Sudanese Patients

There is scarce data on circulation of genetic subtypes of HIV-1 in South Sudan due to decades of civil war. In this study, phylogenetic analysis of 10 strains collected from HIV-1-infected South Sudanese patients was performed. Partial pol and env viral gene analysis classified sequences as subtype C (n = 4), subtype D (n = 4), and partially unclassifiable recombinants (n = 2), interspersed within the phylogenetic tree with those from other African countries. These results indicate an exchange of viral strains between South Sudan and both neighboring and distant territories. The movements of populations across Sudan's borders during the civil war have probably played an important role in circulation of subtypes not only in South Sudan but also in other African states

Short-and long-term immunological responses in chronic HCV/HIV co-infected compared to HCV mono-infected patients after DAA therapy

Background: Direct-acting antivirals (DAAs) treatment, although highly efficacious for the treatment of hepatitis C virus (HCV) infection, may not completely reconstitute the HCV-mediated dysregulated immune system, especially in patients co-infected with human immunodeficiency virus (HIV) and HCV. Objectives: We aimed to evaluate the impact of HCV eradication following DAA therapy on the immune system and liver disease improvement through comparative monitoring of 10 HCV mono-infected and 10 HCV/HIV co-infected patients under combined antiretroviral therapy (cART). Early and late longitudinal phenotypic changes in peripheral blood mononuclear cell (PBMC) subsets, T-cell activation, differentiation and exhaustion, as well as inflammatory biomarkers, indoleamine 2-3 dioxygenase (IDO) activity, and liver stiffness, APRI and FIB-4 scores were assessed. Materials and Methods: Samples were obtained at baseline (T0), week 1 (T1), week 2 (T2), week 12 (T3, end of treatment, EOT), and month 9 (T4, end of follow-up, 36 weeks post EOT). Results: All patients achieved a sustained virological response (SVR 12) after DAA treatment. Overall, changes of the T-cell immune phenotypes were greater in HCV/HIV co-infected than in HCV mono-infected, due to an increase in CD4+ and CD8+ T-cell percentages and of CD8+ T-cell activation and memory markers, in particular at the end of follow-up. On the other end, HCV mono-infected showed changes in the activation profile and in the memory CD4+ T-cell compartment. In HCV/HIV co-infected, a decrease in the IDO activity by DAA treatment was observed; conversely, in HCV mono-infected, it resulted unmodified. Regarding inflammatory mediators, viral suppression was associated with a reduction in IP-10 levels, while interferon regulatory factor (IRF)-7, interferon (IFN)-β, and interferon (IFN)-γ levels were downregulated during therapy and increased post therapy. A decrease in liver stiffness, APRI, and FIB-4 scores was also observed. Conclusions: Our study suggests that, although patients achieved HCV eradication, the immune activation state in both HCV mono-infected and HCV/HIV co-infected patients remains elevated for a long time after the end of DAA therapy, despite an improvement of liver-specific outcomes, meanwhile highlighting the distinct immunophenotypic and inflammatory biomarker profile between the groups of patients

Control of SHIV-89.6p infection of cynomolgus monkeys by the HIV-1 tat protein vaccine

Vaccine strategies aimed at blocking virus entry have so far failed to induce protection against heterologous viruses. Thus, the control of viral infection and the block of disease onset may represent a more achievable goal of human immunodeficiency virus (HIV) vaccine strategies. Here we show that vaccination of cynomolgus monkeys with a biologically active HIV-1 Tat protein is safe, elicits a broad (humoral and cellular) specific immune response and reduces infection with the highly pathogenic simian-human immunodeficiency virus (SHIV)-89.6P to undetectable levels, preventing the CD4+ T-cell decrease. These results may provide new opportunities for the development of a vaccine against AIDS

Live attenuated simian immunodeficiency virus prevents super-infection by cloned SIVmac251 in cynomolgus monkeys.

The ability of a live attenuated simian immunodeficiency virus (SIV) to protect against challenge with cloned SIVmac251/BK28 was evaluated in four cynomolgus macaques. The intravenous infection of the C8 variant of the SIVmac251/32H virus, carrying an in-frame 12 bp deletion in the nef gene, did not affect the CD4+ and CD8+ cell counts, and a persistent infection associated with an extremely low virus burden in peripheral blood mononuclear cells (PBMCs) was established. After 40 weeks, these monkeys were challenged intravenously with a 50 MID50 dose of SIVmac251/BK28 virus grown on macaque cells. Four naive monkeys were infected as controls. Monkeys were monitored for 62 weeks following challenge. Attempts to rescue virus from either PBMCs or bone marrow from the C8-vaccinated monkeys were unsuccessful, but in two cases virus was re-isolated from lymph node cells. The presence of the SIV provirus with the C8 variant genotype maintaining its original nef deletion was shown by differential PCR in PBMCs, lymph nodes and bone marrow. Furthermore, in contrast to the control monkeys, the vaccinated monkeys showed normal levels for CD4+ and CD8+ cells, minimal lymphoid hyperplasia and no clinical signs of infection. Our results confirm that vaccination with live attenuated virus can confer protection. This appears to be dependent on the ability of the C8 variant to establish a persistent but attenuated infection which is necessary for inducing an immune response, as suggested by the persistence of a strong immune B cell memory and by the over-expression of interleukin (IL)-2, interferon-gamma and IL-15 mRNAs in PBMCs of C8-vaccinated monkeys but not in those of control monkeys