The antisense protein of HTLV-2 positively modulates HIV-1 replication

Abstract

Unlike HTLV-1, HTLV-2 does not induce leukemia and has been tentatively associated with an HTLV-1-associated myelopathy-like disorder. It has been reported that HTLV-2/HIV-1 co-infected patients progress less rapidly to AIDS than HIV-1-infected individuals. Tax2 has been suggested to mediate this protective state by inducing MIP-1α expression and blocking HIV-1 infection. As cells from HTLV-2-infected individuals mainly express Antisense Protein 2 (APH-2), our objective was to determine if this protein might also intervene in controlling HIV-1 replication in dually infected individuals. Using Jurkat cells, we first demonstrated that both APH-2 and HBZ, the HTLV-1 analogue, equally induced MIP-1α in unstimulated and stimulated Jurkat T cells. To assess if APH-2 might directly affect HIV-1 replication, a full length luciferase-expressing proviral DNA was tested in Jurkat cells. Surprisingly, upon co-transfection with an APH-2 expression vector, an increase in luciferase activity was observed, while HBZ expression rather led to reduced reporter gene expression. Western blot analyses and ELISA assay further indicated that HIV-1 p24 levels were more important in APH-2-expressing cells. To determine if APH-2 was directly modulating HIV-1 LTR activity, both NF-B and NFAT were tested in stimulated Jurkat cells. Unexpectedly, HBZ and APH-2 inhibited NF-B and NFAT activation, albeit at different extent. In addition, LTR activation was also inhibited by both antisense proteins although APH-2 had a more modest effect. Our results thus highlight the complex interplay between HTLV antisense transcript-encoded proteins and HIV-1 expression and further studies will be required to determine the potential impact of APH-2 in HTLV-2/HIV-1-infected individuals.

Applications of the FIV Model to Study HIV Pathogenesis

“…In 1988, Miller [ 96 ] made the observation that there was also potential to encode a peptide product from an RNA transcribed from the minus strand of the provirus. Since then, there have been a number of reports providing evidence for predicted RNA and protein products from the minus strand in HIV-1 [ 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 ], SIV [ 107 ], FIV [ 108 ], and in the deltaretrovirus, BLV [ 109 ]. In FIV, there are several potential short open reading frames that may be translated from a negative strand message.…”

HTLV-2 Encoded Antisense Protein APH-2 Suppresses HIV-1 Replication

“…We also observed that there is a reduction in the expression of both proteins when they are transfected together, as compared to the protein expression when they are transfected individually. To the best of our knowledge, only one prior study by Torresilla et al [ 23 ] investigated the role of APH-2 in HIV-1 replication. The authors reported increased MIP1α levels along with the inhibition of NF-kB and NFAT in the presence of APH-2, but observed positive modulation of full-length HIV-1 luciferase expression [ 23 ].…”

“…To the best of our knowledge, only one prior study by Torresilla et al [ 23 ] investigated the role of APH-2 in HIV-1 replication. The authors reported increased MIP1α levels along with the inhibition of NF-kB and NFAT in the presence of APH-2, but observed positive modulation of full-length HIV-1 luciferase expression [ 23 ]. Even though the study reported increased expression of MIP1 α, downregulation of NF-kB and NFAT supposedly supports the negative role of APH-2 on HIV-1 replication.…”

“…The regulatory proteins Tax and Rex of HTLV can recognize and bind to the respective cognate sites of HIV-1 Tat and Rev, resulting in the functional replacement for HIV-1 regulatory proteins [ 19 ]. Studies have also reported that HTLV Tax protein alters chemokine expression and impacts HIV-1 disease progression [ 13 , 16 , 18 , 20 , 21 , 22 , 23 ]. Similarly, the CREB transcription factor, which is effectively important in HTLV transcription, was also found to play a key role in the HIV-1 Tat-mediated transcription [ 24 , 25 , 26 ].…”

Applications of the FIV Model to Study HIV Pathogenesis

“…In 1988, Miller [92] made the observation that there was also potential to encode a peptide product from an RNA transcribed from the minus strand of the provirus. Since then, there have been a number of reports providing evidence for predicted RNA and protein products from the minus strand in HIV-1 [93][94][95][96][97][98][99][100][101][102], SIV [103], FIV [104], and in the deltaretrovirus, BLV [105]. The use of neurovirulent strains of FIV has also allowed for the investigation of neuropathogenic effects on the peripheral nervous system (PNS) as a model of HIV distal symmetric polyneuropathy (DSP), demonstrating rapid onset of peripheral neuropathy in FIV infected cats with axonal injury, macrophage activation, and detection of virus within the nerve [50,132].…”