Immunological and Neurological Signatures of the Co-Infection of HIV and HTLV: Current Insights and Future Perspectives

Abstract

The human retroviruses HIV and HTLV-1/HTLV-2 are transmitted through similar pathways but result in markedly different diseases. This review delineates the immune-mediated mechanisms by which HTLVs influence HIV pathology in co-infected individuals. In the context of HIV co-infection, HTLV-1/HTLV-2 alter the cellular microenvironment to enhance their own survival while simultaneously impeding the progression of HIV. Despite the extensive body of literature on the biological and clinical implications of retroviral co-infections, decades of research have been marred by controversy due to several flawed epidemiological studies and anecdotal reports lacking robust statistical and scientific backing. Nevertheless, recent systematic and well-designed research has led to a growing consensus supporting at least three key conclusions: (1) co-infections of HIV-1 and HTLV-1 are frequently observed in patients with elevated CD4⁺ T-cell counts who present with lymphoma or neurological complications; (2) HIV-1 and HTLV-2 co-infections have been associated in some instances with a "long-term non-progressor" phenotype; (3) the differential function and/or overexpression of the HTLV-1 and HTLV-2 Tax proteins are likely crucial in the clinical and immunologic outcomes of HIV/HTLV-1 and -2 co-infections. The present review will provide a comprehensive account of research on retroviral co-infections, focusing particularly on their clinical manifestations and associated pathological features.

Keywords: HIV; HTLV; co-infection; immune response; neurological disorder.

Figure 1

Dysregulation of CD4⁺ T cells and inflammation in HIV and HTLV-1 co-infected patients. The presence of both HIV and HTLV-1 in an individual’s immune system gives rise to a multifaceted immune dysregulation, marked by a paradoxical expansion of CD4⁺ T cells, the presence of chronic inflammation, and an escalated disease burden. Despite elevated CD4⁺ counts, immune function is impaired due to ongoing activation and exhaustion. During HTLV transcription, the Tax protein is upregulated in the presence of HIV through the action of nuclear factor kappa B (NF-κB). This upregulation mechanism is similar to that of cytokines such as interleukin. Within the nucleus, Tax assembles and modifies subcellular structures called Tax nuclear bodies (Tax NBs), where it enhances NF-κB transcriptional activity to its maximum potential. Graphics created by BioRender.com.

Figure 2

Neurological impact of HIV and HTLV-1 co-infection. The impact of HIV and HTLV-1 co-infections on the nervous system is significant, manifesting as a complex interplay of neuroinflammation, immune dysregulation, and neurodegeneration. While HIV is known to cause HAND due to chronic inflammation and direct neuronal toxicity, HTLV-1 is linked to HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive neuroinflammatory disorder affecting the spinal cord. HAM/TSP is the most common neurological manifestation of HTLV-1 and HIV co-infections. Astrocytes are the most abundant cell type in the brain and the only source of HIV and HTLV-1. HIV from infected astrocytes egresses, likely through trafficking of CD4⁺ T cells, into peripheral organs, as indicated by the detection of HIV DNA/RNA. Graphics created by BioRender.com.

Figure 3

Exploring the pathogenesis of HAM/TSP and its impact on HTLV-1-induced neurological effects. This figure explores the pathogenesis of HAM/TSP and highlights the neurological effects induced by HTLV-1 infection, with a particular focus on individuals co-infected with HIV. HTLV-1 is associated with a range of immune-mediated disorders and lymphoproliferative malignancies, with ATL and HAM/TSP being the most prominent consequences. These conditions are the result of a highly selective process, occurring in only a small fraction of individuals infected with HTLV-1 or co-infected with both HTLV-1 and HIV. HTLV-1 causes lymphoproliferative malignancies and many immune-mediated disorders. ATL and HAM/TSP are the consequence of a highly selective process that occurs in only a fraction of infected individuals or those co-infected with HTLV and HIV. The figure further illustrates the role of the HTLV-1 Tax protein, which plays a key role in the pathogenesis of these disorders. The Tax protein activates HIV replication by interacting with the HIV-1 Long Terminal Repeat (LTR), which can lead to enhanced viral replication in co-infected individuals. Graphics created by BioRender.com.