Tat HIV-1 Primary and Tertiary Structures Critical to Immune Response Against Non-homologous Variants

Abstract

Clinical studies show that in the absence of anti-retroviral therapy an immune response against the human immunodeficiency virus type 1 (HIV-1), transacting transcriptional activator (Tat) protein correlates with long term non-progression. The purpose of this study is to try to understand what can trigger an effective immune response against Tat. We used five Tat variants from HIV strains identified in different parts of the world and showed that mutations of as much as 38% exist without any change in activity. Rabbit sera were raised against Tat variants identified in rapid-progressor patients (Tat HXB2, a European variant and Tat Eli, an African variant) and a long term non-progressor patient (Tat Oyi, an inactive African variant). Enzymelinked immunosorbent assay (ELISA) results showed that anti-Tat Oyi serum had the highest antibody titer and was the only one to have a broad antibody response against heterologous Tat variants. Surprisingly, Tat HXB2 was better recognized by anti-Tat Oyi serum compared with anti-Tat HXB2 serum. Western blots showed that non-homologous Tat variants were recognized by antibodies directed against conformational epitopes. This study suggests that the primary and tertiary structures of the Tat variant from the long term non-progressor patient are critical to the induction of a broad and effective antibody response against Tat.

Human Immunodeficiency Virus Type 1 Subtype C Tat Fails To Induce Intracellular Calcium Flux and Induces Reduced Tumor Necrosis Factor Production from Monocytes

“…We also observed that at all concentrations tested, there was no significant difference between the three variants except at 400 nM, the highest concentration tested where both subtype C Tat proteins had a higher activity (data not shown). This difference agrees with previously published data using different cell lines (28,44,57,66 (Fig. 1B) and Tat 96Bw (data not shown) elicited a transient increase in [Ca 2ϩ ] i in monocytes that returned to baseline 1 minute after the initial flux.…”

“…However, recent research has shown that the different genetic subtypes and recombinant forms of HIV-1 have biological differences with respect to transmission, replication, and disease progression (14,47,74,85). Moreover, different subtypes of Tat have different in vitro effects (17,18,27,28,57,62,66,67,76).…”

“…Most studies analyzing the effect of Tat on either HIV-1 or host gene expression have used a truncated 86-residue HIV-1 subtype B Tat, although HIV-1 subtype C is the most prevalent globally (38) and its Tat protein has 101 residues (57,58,66). These studies have shown that Tat is secreted from unruptured, HIV-1-infected lymphoid (21,30) and myeloid (81) cells and is found in the sera of infected individuals (90,92) where it has a variety of effects on a number of different cell types (reviewed in reference 43).…”

HIV-1 Tat Addresses Dendritic Cells to Induce a Predominant Th1-Type Adaptive Immune Response That Appears Prevalent in the Asymptomatic Stage of Infection

“…Indeed, previous data showed that native Tat enters MDDC, induces their maturation, and promotes their capacity of presenting Ag through the preferential development of a Th1-type immune response (15). This body of evidence prompted us to further investigate the apparent intrinsic adjuvanticity of Tat by exploring the effects of the native, wt Tat protein compared with those of cys22 Tat, a naturally occurring Tat mutant originated from a long-term non-progressor individual (31), which induced high titers of antiTat Ab (32,33).…”

HIV-1 Tat-Based Vaccines: An Overview and Perspectives in the Field of HIV/AIDS Vaccine Development

“…Another important feature of Tat rendering it a relevant vaccine antigen is the conservation of its immunogenic regions among the HIV-1 M group at the sequence, functional, and conformational level [120,142,151,152,154,163]. Indeed, the Tat protein of 86 aa from a clade B lab-adapted HIV-1 virus (HTLV-IIIB strain, clone BH-10) isolated more than 20 years ago [164] is very well recognized by sera from African individuals infected with different virus clades, including clade C, which is responsible for more than half of new HIV-1 infections worldwide [165], with similar prevalence and epitope mapping titers of anti-Tat antibodies [120].…”