Human Immunodeficiency Virus (HIV), the etiology of the Acquired Human Immunodeficiency Syndrome (AIDS), caused 1.3 million of new infections and 630,000 AIDS-related deaths in 2024, to record 40.8 million (37.0 million–45.6 million) people living with HIV (PLWH).1

Currently, 77 % of the total infected population have access to the Antiretroviral Therapy (ART). Consequently, the incidence of HIV-related opportunistic infections has been significantly reduced.1 Nevertheless, high-risk groups among PLWH still exhibit high rates of oropharyngeal and esophageal candidiasis,2 bacterial pneumonia,3 herpes zoster4 and tuberculosis.5

Moreover, HIV is associated with an increased risk of cancer development, which is a leading cause of HIV-associated death.6 Cancers directly associated with T-cell immunodeficiency are classified as AIDS-Defining Cancers (ADCs), including Kaposi Sarcoma (KS), Non-Hodgkin Lymphoma (NHL), and cervical cancer. Conversely, non-AIDS-Defining Cancers (NADCs) can occur in both HIV-positive and HIV-negative individuals, although their incidence is higher in people living with HIV.7

Forty different types of NADCs have been recognized, with approximately half of them being associated with oncogenic viruses such as Epstein-Barr, human papillomavirus and hepatitis B and C viruses. These cancers with infectious etiology such as anal, vulvar, vaginal, Hodgkin lymphoma and liver malignancies exhibit high incidence. NADCs without infectious etiology include mesothelial and soft tissue tumors, multiple myeloma and lung cancer. Notably, people living with HIV show higher progression and mortality rates for these malignancies compared to the HIV-negative population.8

In this review, we focus on the molecular mechanisms associated with the development of lung cancer as a NADC of clinical relevance. This multifactorial malignancy requires continued research to elucidate its mechanisms of pathogenesis and identify risk factors to implement targeted therapies and preventive strategies.

This article is a descriptive review. A comprehensive literature search was conducted in the databases PubMed and Google Scholar. The search focused on key terms related to HIV infection and cancer pathogenesis, including HIV, cancer, oncogenic HIV proteins, lung cancer, non-AIDS-defining cancers, pathogenesis, etiology, and molecular mechanisms. The search was primarily limited to articles published within the last 10-years and written in English. Review articles, epidemiological studies, and treatment-focused studies were excluded during the initial search to prioritize original research addressing molecular and pathogenic mechanisms. Articles were selected based on their relevance to the scope of the review.

HIV is an enveloped lentivirus that primarily targets CD4+ cells expressing chemokine receptors, particularly CCR5 and CXCR4, which serve as coreceptors during viral entry. The envelope proteins gp120 and gp41 mediate receptor recognition and fusion of the viral envelope with the plasma membrane, allowing entry of the nucleocapsid.9 Once internalized, the viral RNA is reverse-transcribed into double-stranded DNA while the nucleocapsid migrates to the nucleus. The viral DNA is subsequently imported through nuclear pores and integrated into the host genome. During the late stage of the replication cycle, viral genes are transcribed, the genome is replicated, and newly assembled virions are released from the infected cell.10

Virions using CCR5 as a coreceptor (R5 viruses) initially target memory CD4+ T-cells, which are enriched in mucosal tissues. This early phase of infection results in a massive CD4+ T-cell destruction by direct viral cytopathic effects, cytotoxic T-lymphocyte-mediated killing, and bystander apoptosis induced by Env-mediated signaling. Acute HIV infection is associated with viral loads ranging from 104 to 107 RNA copies/mL11 and leads to the establishment of viral reservoirs, which consist of latently infected cells harboring integrated replication-competent proviruses.

The HIV reservoir is primarily established in resting CD4+ T-cells, which become infected during the transition from an activated to a quiescent state, as well as in myeloid cells residing in different tissues. Accordingly, major viral reservoirs have been identified in the bone marrow,12 lymph nodes, the gut-associated lymphoid system, spleen, thymus, and central nervous system.13,14

Even though ART is effective in reducing plasma viremia to undetectable levels and has improved the quality of life and expectancy for HIV-infected individuals, it does not eliminate the virus from the latently infected reservoir, which carries inducible proviruses capable of reactivation.15 Sampling of different CD4+ T-cell subsets from lymph nodes, Gut Associated Lymphoid Tissue (GALT) and peripheral blood mononuclear cells has revealed that these are active anatomical compartments functioning as sanctuaries for HIV persistence.16 Furthermore, HIV DNA has been detected in specialized macrophage populations such as Kupffer cells, alveolar macrophages and microglia, as well as in mucosal cells of the penile urethra and vagina, contributing to the complexity and heterogeneity of the HIV reservoir.17

In addition to replication-competent proviruses, some cells harbor defective proviral genomes with internal deletions. Although these defective proviruses are incompetent to produce infectious viruses, they can express viral proteins that contribute to chronic inflammation and T-cell exhaustion. In consequence, there exist increased risk to develop HIV-associated comorbidities such as cardiovascular disease, neurodegeneration and cancer.18–20

The HIV genome encodes the Gag, Pol and Env genes which express structural, regulatory and accessory proteins (Fig. 1). Among the regulatory proteins, Tat (trans-activator of transcription) and Rev (regulator of RNA splicing) control viral gene transcription, while accessory proteins such as Nef (Negative regulating factor), Vif (Viral infectivity factor), Vpr (Virus protein r) and Vpu (Virus protein unique) regulate replication, viral budding, immune evasion and pathogenesis.21 Interestingly, the envelope protein gp120, Nef and Tat have been implicated in HIV-associated oncogenesis.

Fig. 1.

HIV-1 structural, regulatory and accessory proteins. The Gag gene encodes the structural proteins matrix (p17), capsid (p24) and nucleoprotein (p7), in addition to p6 (not shown) that mediates viral release. The Pol gene encodes the enzymes Reverse Transcriptase (RT), Integrase (IN) and Protease (PR). The Env gene encodes the envelope glycoproteins gp120/gp41. Created with BioRender.

Tat is a small regulatory protein that increases RNA polymerase II activity during viral genome transcription and downregulates MHC-I expression, contributing to immune evasion and viral persistence. It is secreted at high concentrations in the supernatants of HIV-infected lymphocytes, as well as in serum and cerebrospinal fluid from patients, even under viral control with antiretroviral therapy.22

Tat has also been linked to modulation of the Tat-Interacting Protein 30 (TIP30), a known tumor suppressor involved in regulating apoptosis, proliferation, metastasis, angiogenesis, DNA repair, and tumor metabolism in various cancers, including Hepatocellular Carcinoma (HCC), colorectal carcinoma, glioma, breast cancer, laryngeal squamous cell carcinoma, esophageal carcinoma, lung cancer, among others.23

In hepatocellular carcinoma, loss of TIP30 promotes Epithelial-Mesenchymal Transition (EMT). During the EMT the transcription factor Snail is overexpressed; it has been associated with invasive breast cancer cells since it recruits a repressor complex to inhibit E-cadherin transcription.24 Nuclear translocation of Snail is facilitated by its interaction with importin-β2. Tat interacts with importin-β2 increasing nuclear localization of Snail leading to EMT, enhanced cell motility and poor prognosis by metastasis.25,26

The envelope glycoproteins gp120 and gp41 are membrane-associated proteins, although gp120 can also be released in a soluble form stimulating neighboring cells and altering signaling pathways related to immune response, cell viability and cell cycle regulation.27,28 Particularly, gp120 induces IL-6 production and expansion of myeloid derived suppressor cells with a phenotype CD11b+, CD33+, HLA-DR-/low, and pSTAT3hi, which are associated with expansion of regulatory T-cells and immunosuppression.29 Additionally, gp120 induces apoptosis and disrupt the cell cycle in epithelial, lymphoid and neuronal cells by upregulating cyclin dependent kinase 1 and proapoptotic effectors such as Bax, Fas/FasL, caspase 3 and caspase 8.30,31

Soluble gp120 has also profibrotic activity in human hepatic stellate cells through interaction with CXCR4 and subsequent ERK1/2 phosphorylation, triggering collagen I expression. This process possibly accelerate liver fibrosis in HIV positive individuals, especially those coinfected with hepatitis C virus.32

In epithelial cells, both gp120 and Tat upregulate markers of EMT, such as N-cadherin and vimentin, along with downregulation of E-cadherin and cytokeratin.33 Immunohistochemical analysis of cervical cancer tissues from HIV-positive women coinfected with Human Papillomavirus (HPV) show diminished expression of E-cadherin and cytokeratin, whereas vimentin is increased with respect to tissues from HIV-negative patients, suggesting that gp120 and Tat induce EMT and facilitate the progression of HPV-associated cervical lesions.33

On the other hand, the regulatory protein Nef is expressed early after infection and manipulates host cell processes to increase viral replication and persistence. Nef modulates T-cell activation by internalization and lysosomal degradation of CD4 and CD28. Promotes indirectly viral infectivity of CD4+T-cells through production of CCL2 and CCL4 in macrophages, which results in chemotaxis and activation of T-lymphocytes, which become permissive to HIV (Fig. 2).34 Nef also contributes to immune evasion avoiding antigen presentation by interfering of the trafficking of HLA-I, reducing recognition of infected cells by cytotoxic lymphocytes.35 Its role in modulating stability of viral and cellular proteins that participate in virus replication via the ubiquitin proteasome system has been described by proteomic analysis.36 Actually, Nef interacts with the ubiquitin E3 ligase E6AP to induce p53 ubiquitination and proteasomal degradation.37 P53 is a transcriptional regulator in response to DNA damage induced by ultraviolet light, gamma radiation and carcinogens. Loss of p53 function impairs cell cycle control and apoptosis, allowing genetically damaged cells to survive and accumulate oncogenic mutations.38

Fig. 2.

HIV entry is mediated by the interaction of the viral envelope proteins gp120/gp41 with the host cell molecules CD4 (primary receptor) and CCR5 or CXCR4 (main coreceptors). After the Reverse Transcriptase (RT) enzyme synthesize the viral DNA and it is imported to the nucleus, the integrase inserts the viral DNA into the host-cell chromosomes. The transcription, replication and translation of the viral genome are mediated by hijacked cellular components, which allows for the synthesis of all necessary components to assemble a new viral progeny. HIV replication is optimized by processes such as immune evasion and cell survival. The viral protein Tat not only increases viral transcription but also reduces the expression of MHC-I in epithelial and lymphoid cells. Both Tat and gp120 induce expression of vimentin while E-cadherin is downregulated, an event associated with the EMT. In addition, soluble gp120 induces the synthesis of IL-6, which indirectly promotes the expansion of Treg lymphocytes, upregulates CDK1 (to alter the cell cycle), and induces the expression of proapoptotic molecules. Nef modulates the stability of both viral and cellular proteins by ubiquitination (e.g., inducing p53 degradation via the proteasome) and increases the expression of the enzyme ATIC, which upregulates the proto-oncogene Myc in lung cancer. Created with BioRender.

In addition, Nef increases the expression of the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), which participates in the purine biosynthetic pathway.36 ATIC is upregulated in myeloma and HCC. Also, this enzyme is overexpressed in advanced stages of lung adenocarcinoma and promotes cell growth and migration through upregulation of the proto-oncogen Myc.39

Lung cancer, as all types of cancers, is multifactorial and particularly, in people living with HIV, immunosuppression, chronic inflammation, smoking and the oncogenic HIV proteins are interconnected triggering factors. In the following sections we summarize epidemiology, evidence of HIV persistence in lungs and molecular mechanisms associated with lung cancer in PLWH.

Lung cancer is the most common NADC and the leading cause of cancer-related deaths in PLWH.40,41 Histologically, it is classified in two main types: Non-Small Cell Lung Cancer (NSCLC) and small cell lung cancer. NSCLC is a heterogeneous group of epithelial malignancies that account for 86 %–94 % of lung cancers; the main subtypes are adenocarcinoma, squamous cell carcinoma and large cell carcinoma.42 Adenocarcinoma is the most frequent subtype (30 %–50 %).

The incidence of lung cancer in patients with HIV represents a notable disparity compared to the general population. Epidemiological studies indicate that PLWH have 1.5–3-fold increased risk of developing lung cancer, compared with the HIV-negative population.42,43

A study using data from the multicenter CoRIS Spanish cohort (2004‒2021) reported 176 deaths associated with non-AIDS-defining tumors, of which, 36.4 % were related to lung cancer (mortality rate of 0.57, 95 % CI 0.45, 0.73). Lung cancer was associated with a 2-fold increase in mortality in PLWH. The risk of mortality was also higher in association with factors such as coinfection with hepatitis B and C viruses, heterosexual HIV transmission, use of injected drugs, active smoking, and CD4 counts < 500 µL.44

Another study that analyzed data from the HIV/AIDS Cancer Match Study (USA) from 2001 to 2016 estimated a significant decrease in the incidence of lung cancer among individuals with HIV: incidence rates were 124.4 per 100,000 person-years during 2001 to 2003, compared to 58.3 per 100,000 person-years in the period from 2013 to 2016. However, the incidence rates remained 48 % higher in HIV+ individuals than in the general population.42 Such decrease could be associated with increased access to ART; however, immune recovery is incomplete in a proportion of patients and may represent a persistent risk factor for lung cancer. In particular, a low CD4/CD8 ratio, a low nadir CD4+ T-cell count and residual or intermittent viremia despite ART have been associated with higher incidence of this malignancy in PLWH. Moreover, aging and pulmonary infections related to chronic inflammation (e.g., tuberculosis) may also contribute to cancer risk. Of relevance, lung cancer diagnosis in PLWH has been associated with decreased median survival compared with general population (12.4 vs. 22.8-months).41–43

In addition to the gut-associated lymphoid tissue, other long-term HIV reservoirs have been identified.45 Particularly, HIV provirus has been quantified in Bronchioalveolar Lavages (BAL) and Peripheral Blood Leucocytes (PBLs) from patients living with HIV that developed respiratory symptoms. Results revealed higher levels of proviral DNA in BAL derived cells (2971 HIV DNA copies/106 cells), compared to PBLs (391 HIV DNA copies/106 lung cells). Interestingly, viral genome can be detected even in patients receiving nucleoside reverse-transcriptase inhibitors, although with reduced levels (up to 6-fold decrease).46

HIV DNA has also been quantified in BAL from patients without respiratory symptoms, under ART and with a minimum of 3-years of viral suppression. In this case, BAL derived cells showed higher HIV DNA copies than PBMCs (13-fold); particularly, effector memory CD4+T-cells were the principal HIV reservoir. Interestingly, the pulmonary CD4+T-cell population showed an enrichment of CD57+ cells that are associated with immuno-senescence, whereas T-regulatory Foxp3+ cells were also increased. Thirty percent of the patients showed HIV RNA in BAL derived cells, indicating active viral genome transcription.47

Notably, Nef+ cells (CD4+, CD8+ and alveolar macrophages) have been evidenced in BAL from patients with undetectable levels of p24 and genomic RNA. Therefore, persistent expression of HIV regulatory proteins in lung tissue and other anatomical sites contribute to tissue damage, immunosuppression and cancer development.48

The molecular interplay between HIV infection and lung cancer development involves a complex network of viral proteins, host signaling pathways, and epigenetic regulators (Fig. 3 and Table 1). Proteins such as Tat, Nef, and gp120 modulate oncogenic processes, including cell cycle dysregulation, apoptosis inhibition, epithelial-mesenchymal transition, angiogenesis, and immune evasion allowing virus persistence. Persistent viral reservoirs within lung tissue sustain local inflammatory and immunosuppressive microenvironments that stimulate cell transformation. Concurrently, HIV integration into host DNA and increased gene methylation contribute to the silencing of tumor suppressor genes. Also, extracellular vesicles carrying viral components maintain pro-tumorigenic signaling.

Fig. 3.

Interacting network of altered genes in lung tissues and cells derived from lung malignancies from PLWH. The list of genes from Table 1 was analyzed in STRING, Version 12.0. Two clusters were identified that, as expected, are related with cancer development and the TNF signaling pathway involving proinflammatory genes. As mentioned in the main text, *PTEN, *SIX1 and p16INK4a (also known as *CDKN2A) are potential biomarkers of lung cancer prognosis.TP53 is synonym of p53.

Future research should prioritize the construction of comprehensive interaction networks to enable the identification of molecular causal factors driving lung cancer progression in PLWH. Such integrative approaches may help to identify early prognostic biomarkers. At present, molecules such as PTEN, SIX1 and p16INK4a have been described as prognostic biomarkers in human lung cancer, while Ago2 and DICER1 might be considered as molecules with potential prognostic application in this type of malignancy. From a therapeutic perspective, focusing on these biomarkers may provide a rationale for future studies to explore new strategies to combine antiretroviral drugs with targeted inhibitors of key effectors in oncogenic signaling pathways. In addition, public-health campaigns could be developed to emphasize the harmful effects of smoking, particularly among PLWH, to reduce predisposing factors for lung cancer.

BRID, FNJ and RTE designed, collected data and wrote the manuscript; RHDL contributed to writing and prepared illustrations. All authors contributed to the article and approved the submitted version.

This work was supported by the Secretaría de Ciencia, Humanidades, Tecnología e Innovación (SECIHTI), Mexico, project CBF2023-2024-2356.

The data that support the findings of this study are available from the corresponding author upon reasonable request.