Antigen Presenting Cell-Mediated HIV-1 Trans Infection in the Establishment and Maintenance of the Viral Reservoir

Abstract

Despite potent antiretroviral therapy, an HIV-1 reservoir persists that represents a major barrier to a cure. Understanding the mechanisms by which the HIV-1 reservoir is established and maintained is critical for the discovery of effective treatments to significantly reduce or eliminate the viral reservoir. In addition to cis infection, in which HIV-1 directly infects target CD4⁺ T cells, cell-to-cell transmission, or trans infection, can also occur. HIV-1 trans infection is significantly more efficient than cis infection, mostly due to the occurrence of multiple infections per cell during transfer. Additionally, trans infection is efficient even in the presence of ART and/or neutralizing antibodies. Cell-to-cell transmission is mediated by CD4⁺ T cells and professional antigen presenting cells (APC). Here we focus on APC, i.e., myeloid dendritic cells, B lymphocytes, and monocytes/macrophages, that bind, internalize, and transfer HIV-1 to target CD4⁺ T cells via various proposed mechanisms. We assess the potential impact of trans infection on the establishment and maintenance of the HIV-1 reservoir including its role in disease progression. We consider the natural interactions between APC and CD4⁺ T cells in vivo that HIV-1 may hijack, allowing for the highly efficient trans infection of CD4⁺ T cells, maintaining the viral reservoirs in tissue despite undetectable plasma viral loads in peripheral blood. We propose that these modes of viral pathogenesis need to be addressed in potential cure strategies to ensure eradication of the viral reservoir.

Figure 1.

Schematic depicting APC and CD4⁺ T cells interactions with proposed HIV-1 trans infections. (A) At the site of infection in sexually transmitted cases, macrophages (Mφ) and iDC bind HIV-1 via DC-SIGN or DC-SIGN and Siglec-1, respectively, which they transfer to target CD4⁺ T cells. (B) Lymph node areas defined. CCL19/21 chemokine gradient guides DC to paracortex (T cell zone). (C) Subcapsular macrophages (SCM) in the SCS bind HIV-1 via Siglec-1 and trans infect CD4⁺ T cells in the paracortex. (D) Naïve B cells (B_N) survey SCM for their cognate antigen and bind HIV-1 presented on SCM via DC-SIGN. Once activated, B cells upregulate CCR7 and travel to the B:T cell border by the CCL19/21 chemokine gradient. At the B:T cell border, B cells survey CD4⁺ T cells. B cells may transfer virus to T_N cells while surveying or to pre-T_FH cells during their antigen-specific interaction. B cells and now fully differentiated T_FH cells can subsequently form GC where further B cell-mediated trans infections occur. (E) In the paracortex, mDC that have internalized HIV-1 survey CD4⁺ T cells for their cognate T_N cell and transfer virus during these interactions. iDC that migrate into SLO bind HIV-1 via DC-SIGN and trans infect CD4⁺ T cells. Figure created with BioRender.com.