The Excessive Presence of TGFb During the Primary Immune Response Against HIV

TGFβ and Its Role in Localized Inflammation and Immune Regulation

TGFβ is critical in facilitating tissue repair during periods of localized inflammation. It generates a chemotactic gradient for T cells and monocytes, promotes their activation, and then downregulates their activity through a feedback loop. The contradictory effects of TGFβ on immune function can be attributed to its ability to activate resting, immature immune cells, such as T cells, while simultaneously inhibiting memory or activated cells of the same lineage.

However, if TGFβ is released inappropriately or accumulates excessively, it can suppress the immune response to subsequent infections. To reach infection sites, immune cells must traverse the endothelial barrier by binding to E-selectin receptors. E-selectin recruits Th1 CD4 cells to inflammation sites but does not affect Th2 cell migration. Th1 cells secrete IL-2, gamma interferon, and IL-12, activating responses against viruses, parasites, and tumors.

TGFβ, Th1/Th2 Imbalance, and HIV Infection

There is an ongoing scientific debate regarding whether HIV-infected individuals lack Th1 cells or preferentially secrete Th2-associated cytokines (IL-4, IL-5, IL-6, IL-10). This theory gains weight from in vivo findings that only Th1 cells selectively enter sites of inflammation. Importantly, TGFβ inhibits the induction of E-selectin on endothelial cells. Circulating E-selectin levels correlate positively with disease progression in AIDS.

Pro-inflammatory cytokines like TNFα and IL-1 promote leukocyte adhesion to endothelial cells. In contrast, mice genetically deficient in TGFβ develop progressive wasting syndromes marked by widespread lymphocyte and macrophage infiltration. The initial lesion in these mice is increased leukocyte adhesion to endothelial veins. If HIV proteins trigger excess TGFβ production, Th1 cells cannot access infected tissues, impairing viral clearance. Thus, the disruption of cytokine reciprocity by viral proteins enhances HIV’s persistence.

TGFβ as a Predictor of Disease Progression

One reliable predictor of HIV disease progression is a defective delayed-type hypersensitivity (DTH) response to recall antigens. TGFβ, secreted by HIV-infected CD4 T cells, inhibits immediate and delayed hypersensitivity reactions. Its presence in cell supernatants correlates with an inability to respond to PPD or tetanus toxoid stimulation.

TGFβ suppresses the development of B cells, cytotoxic T cells, NK cells, and lymphokine-activated killer cells through several mechanisms. First, it downregulates the c-myc gene, suppressing proliferation and promoting apoptosis. Second, it deactivates macrophages, limiting antigen processing and cytokine production. Third, TGFβ inhibits pore-forming protein expression in CD8 cells, compromising their ability to eliminate infected cells. Fourth, it downregulates MHC class I and II antigen expression, impairing both humoral and cellular immune responses. Fifth, it promotes CD8 suppressor cell development, which suppresses antibody secretion.

B Cell Dysregulation and Antibody Isotype Bias

Although hypergammaglobulinemia is an early AIDS marker, the antibodies produced tend to be low-affinity and skewed toward IgG1 and IgA isotypes. TGFβ selectively stimulates IgA secretion, while IL-6—induced by HIV proteins NEF, TAT, and gp120—stimulates IgG1. B cells from HIV-positive individuals proliferate poorly in response to polyclonal activator Staphylococcus aureus Cowan I (SA), a response correlated with TGFβ secretion from infected CD4 cells. Therefore, antibody presence alone is not indicative of a strong primary immune response. SA stimulation tests may complement DTH tests as early immune function indicators in HIV-positive individuals.

TGFβ Inhibition of Chemokine Signaling and Bone Marrow Development

In addition to suppressing immune activation and cell migration, TGFβ—like glucocorticoids—blocks the synthesis of chemotactic HIV receptor antagonists MIP-1α and MIP-1β. It also downregulates the MIP-1α receptor on bone marrow cells. Although effects on CD8-derived MIP-1α/β remain unstudied, TGFβ inhibits CD34 stem cell development in bone marrow following exposure to HIV or soluble gp120.

TGFβ and Cyclosporin A: Shared Immunosuppressive Pathways

TGFβ and Cyclosporin A (CysA) share many immunosuppressive properties. Both inhibit IL-2 gene expression in T cells via a noncanonical octamer-binding site. CysA also promotes TGFβ transcription, which may underlie its immunosuppressive and adverse effects, including hypertension and kidney fibrosis. While CysA blocks the maturation of CD4+CD8+ thymocytes, TGFβ inhibits the transition of double-negative (CD4–CD8–) cells to double-positive (CD4+CD8+). However, CD8 development from surviving double-positive cells continues, whereas CD4 maturation is further impaired. Notably, CD4 T cell numbers increase significantly in TGFβ-deficient mice.

Impact of TGFβ on Thymic Cell Development and HIV Pathogenesis

TGFβ responsible for these thymocyte development effects originates from thymic stromal epithelial cells, which become HIV-infected early post-seroconversion. HIV indirectly induces apoptosis in CD4+CD8+ and CD4+ medullary thymocytes, as these cells are not themselves infected. In SCID-hu mice, depletion of CD4+CD8+ cells is linked to thymic viral load. In pediatric and adult HIV infections, naive CD8 T cells decline at the same rate as CD4 cells.

In advanced disease stages, over 80% of peripheral blood CD8 cells are memory or activated cells, compared to just 5% in uninfected individuals. The inability to regenerate naive CD8 cells leads to a breakdown in cell-mediated immunity. A parallel decline in naive and memory CD4 cells has also been documented. CD4 counts drop steadily at 50 cells/µL per year before symptom onset, suggesting that viral and TGFβ-mediated blocks in T cell development contribute to early immunodeficiency.

TGFβ, Macrophages, and CNS Involvement in AIDS

Macrophages, key HIV targets, may acquire the virus in inflamed mucosal tissues. Activated macrophages release TGFβ, which is implicated in AIDS-related CNS dysfunction. TGFβ upregulates HIV replication in macrophages via poorly understood mechanisms. Typically, macrophages resist infection by T cell-tropic HIV strains. Yet, when treated with physiological TGFβ after infection, these strains replicate similarly to monocyte-tropic strains.

As the disease progresses, monocyte-tropic strains give way to T cell-tropic variants. The former causes significant CD4 depletion in SCID-hu mice without infecting T cells directly. Direct cell-cell interactions between T cells and monocytes are necessary for high HIV replication. TGFβ may enable macrophages to transfer T cell-tropic strains to T cells, accelerating CD4 decline. This cell-to-cell transfer occurs rapidly and may not require free virus particles. TGFβ-stimulated macrophages likely serve as reservoirs for diverse viral genotypes with varying cytopathogenicity.

TGFβ and the Shift Toward Th2-Dominant Responses

TGFβ later deactivates many TNFα-activated cells. In HIV, a Th1-to-Th2 shift in CD4 responses is believed to occur, reducing cell-mediated immunity in favor of humoral responses, which alone are insufficient for viral clearance. TGFβ promotes this shift directly and via IL-10 pathways.

For instance, in cardiac allografts transfected with the TGFβ gene, Th0 cells failed to convert into Th1 cells. TGFβ also induces macrophages to release IL-10, which deactivates macrophages and inhibits TNFα production. IL-10 disrupts dendritic-T cell clustering and promotes cytokine mRNA degradation, while TGFβ suppresses translation. Both also block NF-kB activation by promoting IkBα expression, contributing to long-term antigen-specific anergy in T cells.

TGFβ, IL-10, and Immune Dysfunction in HIV

IL-10 levels are elevated in PBMCs and B cells from HIV-positive individuals, correlating with low CD4 counts and impaired Th1 function. Anti-IL-10 antibodies can restore Th1 responses. Additionally, IL-12 production by Th1 cells is deficient in HIV, although gamma interferon can restore it. However, gamma interferon is itself inhibited by TGFβ, IL-10, and glucocorticoids. TGFβ further blocks IL-12 activity at the cellular level. IL-12 has been trialed clinically to restore cell-mediated immunity in HIV. Chronic stimulation of TGFβ by viral proteins such as TAT, VPR, or gp120 may result in severely compromised immune responses to HIV and opportunistic infections.