The Biology of VPR

Role of VPR in HIV Pathogenesis

VPR is a viral protein specific to primate lentiviruses. Notably, the feline immunodeficiency virus (FIV) lacks a VPR gene, potentially explaining why some infected cats remain asymptomatic. In simian immunodeficiency virus (SIV), VPR deletion mutants still cause AIDS in rhesus monkeys, though the disease progression is significantly attenuated. Monkeys infected with VPR mutants tend to survive longer and exhibit more robust humoral and cell-mediated immune responses than wild-type viruses.

In tissue culture, deletion of NEF or VPR does not impair SIV replication. However, in rhesus monkeys, both NEF and VPR mutants frequently revert to wild-type forms, and this reversion correlates with disease progression. VPR and NEF mutants that do not revert typically result in low viral burden and absence of disease, suggesting strong selective pressure for functional VPR and NEF in HIV infections.

VPR and Viral Latency

Peripheral blood cells from HIV-infected individuals, when cultured in vitro, generally do not produce virus unless activated by antigens, mitogens, or cytokines. Latent infections dominate during the asymptomatic period of AIDS. Although TNF is known to stimulate viral production, this appears limited to the symptomatic phase of the disease. TNF secretion is likely suppressed by glucocorticoids, VPR, and TGF-β, contributing to the extended asymptomatic phase observed in Western populations.

HIV-1 virions contain up to 1,000 VPR proteins, which are released upon virion disintegration (half-life ~2 days). These proteins, along with TAT, may activate viral production from latently infected cells through paracrine or autocrine mechanisms. High local concentrations of extracellular VPR in lymphoid organs may regulate the HIV life cycle, while serum antibodies control circulating VPR levels. A failure to produce high-affinity anti-VPR antibodies—due to nonspecific B cell activation by NEF, TAT, TGF-β, and IL-10—can increase free VPR in the blood and elevate viral titers.

Importantly, although most blood-borne viral particles are non-infectious, their presence strongly correlates with disease severity, suggesting that dead virions contribute to AIDS pathogenesis.

VPR’s Effect on T Cells

VPR prevents primary T cells from becoming chronically infected reservoirs. Only tissue culture-adapted T cell lines maintain chronic viral production. VPR exerts cytolytic effects by inhibiting p34^cdc2 activity, arresting cells in G2 phase, and triggering apoptosis. The dynamics of HIV infection in T cells appear governed by the balance between new infections and the death of previously infected cells.

Studies from the Ho and Shaw groups demonstrate that protease inhibitors rapidly reduce viral titers and restore CD4 T cell counts. Since VPR can inhibit cell cycle progression independently of active viral infection, its clearance following protease inhibitor therapy may allow uninfected T cells to re-enter the cell cycle and proliferate, partially explaining the rapid CD4 T cell recovery observed.

Another mechanism may involve the proteasome. HIV protease inhibitors block chymotrypsin-like activity in the proteasome complex, which normally degrades CD4 molecules. Thus, protease inhibition may lead to CD4 accumulation in both infected and uninfected cells.

VPR and Macrophages

In mononuclear phagocytes, particularly macrophages—which serve as major HIV reservoirs—VPR is essential for efficient viral replication. Unlike T cells, which can integrate proviral DNA without VPR, macrophages rely on VPR to facilitate the nuclear import of viral nucleic acids. VPR deficiency can reduce viral replication in macrophages by up to 1,000-fold.

Glucocorticoids and NF-κB Suppression

Glucocorticoids, similar to cyclosporin, exert immunosuppressive effects. Calcineurin activation counters glucocorticoid-induced apoptosis in T cells, while glucocorticoid-receptor complexes inhibit IL-2 gene transcription via calcineurin-dependent pathways. These receptor complexes also interfere with transcription factors like AP-1, CREB, and NF-κB, blocking their DNA-binding capacity.

Additionally, glucocorticoids stimulate the synthesis of IκBα, which sequesters NF-κB and prevents its activation. NF-κB is essential for transcription of various genes implicated in AIDS pathogenesis, including:

• HIV-1/2, CMV, adenovirus
• Immunoglobulin κ light chain
• T cell receptor α/β chains
• MHC class I/II, β2-microglobulin
• ELAM-1, VCAM-1, ICAM-1
• Type I interferons (e.g., IFN-β)
• GM-CSF, G-CSF, M-CSF
• IL-2, IL-6, IL-8
• TNF-α/β
• C-rel, NF-κB precursor p105
• c-Myc
• Nitric oxide synthase

If VPR and other HIV proteins activate glucocorticoid receptors, they may suppress immunity primarily through NF-κB inhibition. Despite the presence of a glucocorticoid response element (GRE) in the VIF gene, in vivo data do not support increased viral titers following glucocorticoid administration. In fact, dexamethasone and prednisolone reduce HIV gene expression and viral antigen levels and preserve CD4 T cells.

Immunosuppressive Effects of VPR and Glucocorticoids

Dexamethasone inhibits macrophage-mediated CD4 T cell depletion via anti-CD4 antibodies or immune-complexed gp120. It also suppresses CD95 upregulation, a key apoptosis trigger, in a dose-dependent manner. Overall, glucocorticoids either reduce or have no effect on HIV titers and help preserve immune function during the asymptomatic phase of infection.

In Western populations, the asymptomatic phase may extend for over a decade. In contrast, HIV-infected individuals in Africa, often exposed to malaria, tuberculosis, and parasitic infections, typically progress to AIDS within three years. These co-infections elevate TNF and nitric oxide—potent HIV gene activators. Moreover, factors such as malnutrition and chronic stress further accelerate disease progression.

When pro-inflammatory cytokine levels become excessive, tissues may develop glucocorticoid resistance, similar to the resistance observed in asthmatics to inhaled steroids. This resistance disables the physiological feedback mechanisms that generally suppress excessive immune activation and viral replication.

Glucocorticoid Resistance: A Critical Turning Point in AIDS Progression

The emergence of widespread glucocorticoid resistance marks a pivotal event in the transition from chronic HIV infection to clinical AIDS. Without this resistance, HIV infection—despite being chronic—may remain non-lethal. The breakdown of glucocorticoid-mediated immune regulation enables unchecked pro-inflammatory signaling and viral reactivation, ultimately allowing AIDS to manifest.