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January 2005 - November 2014
July 1996 - January 2005
Publications
Publications (223)
Each time the virus starts a new round of expression/replication, even under effective antiretroviral therapy (ART), the transactivator of viral transcription Tat is one of the first HIV-1 protein to be produced, as it is strictly required for HIV replication and spreading. At this stage, most of the Tat protein exits infected cells, accumulates in...
Despite over 30 years of enormous effort and progress in the field, no preventative and/or therapeutic vaccines against human immunodeficiency virus (HIV) are available. Here, we briefly summarize the vaccine strategies and vaccine candidates that in recent years advanced to efficacy trials with mostly unsatisfactory results. Next, we discuss a nov...
Background
Low-level HIV viremia originating from virus reactivation in HIV reservoirs is often present in cART treated individuals and represents a persisting source of immune stimulation associated with sub-optimal recovery of CD4⁺ T cells. The HIV-1 Tat protein is released in the extracellular milieu and activates immune cells and latent HIV, le...
Previous work has shown that the Tat protein of Human Immunodeficiency Virus (HIV)-1 is released by acutely infected cells in a biologically active form and enters dendritic cells upon the binding of its arginine-glycine-aspartic acid (RGD) domain to the α5β1, αvβ3, and αvβ5 integrins. The up-regulation/activation of these integrins occurs in endot...
Antiretrovirals belonging to the HIV protease inhibitor (HIV-PI) class exert inhibitory effects across several cancer types by targeting tumor cells and its microenvironment. Cervical carcinoma (CC) represents a leading cause of morbidity and mortality, particularly in women doubly infected with high-risk human papillomaviruses (HR-HPV) and the hum...
Introduction: Although successful at suppressing HIV replication, combination antiretroviral therapy (cART) only partially restores immune functions and fails to reduce the latent HIV reservoir, thus requiring novel interventions for its intensification.
Areas covered: Here are reviewed therapeutic vaccine candidates that are being developed to thi...
HIV-1 Tat is an essential protein in the virus life cycle, which is required for virus gene expression and replication. Most Tat that is produced during infection is released extracellularly and it plays a key role in HIV pathogenesis, including residual disease upon combination antiretroviral therapy (cART). Here, we review epidemiological and exp...
Introduction: Tat, a key HIV virulence protein, has been targeted for the development of a therapeutic vaccine aimed at cART intensification. Results from phase II clinical trials in Italy (ISS T-002) and South Africa (ISS T-003) indicated that Tat vaccination promotes increases of CD4⁺ T-cells and return to immune homeostasis while reducing the vi...
Flow-chart for the ISS T-002 and ISS T-002 EF-UP studies. One hundred sixty-eight HIV-infected cART-treated volunteers were enrolled in the ISS T-002 trial and randomly allocated to one of the four treatment groups to receive intradermal injections of biologically active HIV-1 Tat protein at the indicated doses without any adjuvant 1 month apart. A...
Anti-Tat Ab persistence by the number of anti-Tat Ab classes over 8 years of follow-up. Kaplan-Meier estimates showing the cumulative probability of anti-Tat Ab durability in ISS T-002 responders (n = 71) stratified according to the number of anti-Tat Ab classes induced by vaccination (1, 2, or 3 classes) up to 412 weeks of follow-up (median follow...
Changes of blood HIV-1 proviral DNA load over baseline in vaccinees stratified by cART regimen during follow-up. Baseline values (left panels) and annual changes (right panels) of HIV DNA levels (expressed as log10 copies/106 CD4+ T-cells) from ISS T-002 study entry in vaccinees stratified by cART regimen are shown. The number of participants teste...
Longitudinal regression analysis of HIV-1 proviral DNA decay in vaccinees stratified by vaccine regimens. Tat vaccine dose-effects on the proviral DNA decay (expressed as log10 copies/106 CD4+ T-cells) by a longitudinal analysis using a random-effects regression model is shown.
Relationship of CD4+ T-cells (A), CD8+ T-cells (B) and HIV-1 proviral DNA in vaccinees during follow-up. Relationships between changes of HIV proviral DNA levels from baseline (log10 copies/106 CD4+ T-cells) and the changes of CD4+ T-cells (A) or CD8+ T-cells (B) from baseline are shown. A generalized estimating equation with adjustment for repeate...
Changes over baseline of CD4+ T-cells stratified by CD4+ T-cell nadir during 8 years of follow-up. Baseline values (left panels) and annual changes over baseline (right panels) from ISS T-002 study entry of CD4+ T cells stratified by CD4+ T-cell nadir are shown. Vaccinees with CD4+ T-cell nadir ≤ 250 cells/μL: n = 20, >250 cells/μL: n = 72. Data ar...
Longitudinal regression analysis of CD4+ T-cells stratified by Tat vaccine regimens. Tat vaccine dose-effects on the increase of CD4+ T cells by days. A longitudinal analysis using a random-effects regression model was performed.
Variations upon time of CD4+ T-cell number stratified according to baseline CD4+ T-cell quartiles. Linear regression mixed effect model for variations upon time of CD4+ T-cell number stratified by baseline CD4+ T-cell quartiles. CD4+ T-cell quartiles at baseline: Q1 <493 (n = 23), Q2 493–600 (n = 24), Q3 601–734 (n = 22) and Q4 >734 (n = 22). Y-axi...
Variations upon time of HIV-1 proviral DNA stratified according to baseline HIV-1 proviral DNA quartiles. Linear regression mixed effect model for variations upon time of HIV-1 proviral DNA (log10 copies/106 CD4+ T-cells) stratified by baseline HIV-1 proviral DNA quartiles. HIV-1 proviral DNA quartiles at baseline: Q1 <2.86 (n = 22), Q2 2.86–3.10 (...
Infection of uterine cervix epithelial cells by the Human Papilloma Viruses (HPV) is associated with the development of dysplastic/hyperplastic lesions, termed cervical intraepithelial neoplasia (CIN). CIN lesions may regress, persist or progress to invasive cervical carcinoma (CC), a leading cause of death worldwide. CIN is particularly frequent a...
Introduction: In spite of its success at suppressing HIV replication, combination antiretroviral therapy (cART) only partially reduces immune dysregulation and loss of immune functions. These cART-unmet needs appear to be due to persistent virus replication and cell-to-cell transmission in reservoirs, and are causes of increased patients’ morbidity...
Background Although combined antiretroviral therapy (cART) has saved millions of lives, it is incapable of full immune reconstitution and virus eradication. The transactivator of transcription (Tat) protein is a key human immunodeficiency virus (HIV) virulence factor required for virus replication and transmission. Tat is expressed and released ext...
Introduction:
Classical approaches aimed at targeting the HIV-1 envelope as well as other structural viral proteins have largely failed. The HIV-1 transactivator of transcription (Tat) is a key HIV virulence factor, which plays pivotal roles in virus gene expression, replication, transmission and disease progression. Notably, anti-Tat Abs are unco...
Background:
The phase II multicenter, randomized, open label, therapeutic trial (ISS T-002, Clinicaltrials.gov NCT00751595) was aimed at evaluating the immunogenicity and the safety of the biologically active HIV-1 Tat protein administered at 7.5 or 30 μg, given 3 or 5 times monthly, and at exploring immunological and virological disease biomarker...
Many attempts have been made or are ongoing for HIV prevention and HIV cure. Many successes are in the list, particularly for HIV drugs, recently proposed also for prevention. However, no eradication of infection has been achieved so far with any drug. Further, a residual immune dysregulation associated to chronic immune activation and incomplete r...
Background
Tat is a key HIV-1 virulence factor, which plays pivotal roles in virus gene expression, replication, transmission and disease progression. After release, extracellular Tat accumulates in tissues and exerts effects on both the virus and the immune system, promoting immune activation and virus spreading while disabling the host immune def...
The role of variable regions of HIV-1 gp120 in immune escape of HIV has been investigated. However, there is scant information on how conserved gp120 regions contribute to virus escaping. Here we have studied how molecular sequence characteristics of conserved C3, C4 and V3 regions of clade C HIV-1 gp120 that are involved in HIV entry and are targe...
The p16 (p16) tumor-suppressor protein is a biomarker for activated expression of human papillomavirus oncogenes. However, data are insufficient to determine whether p16 overexpression predicts the risk for progression of low-grade cervical intraepithelial neoplasia (CIN). This study was aimed at evaluating the risk for progression to CIN2 or worse...
Use of Env in HIV vaccine development has been disappointing. Here we show that, in the presence of a biologically active Tat subunit vaccine, a trimeric Env protein prevents in monkeys virus spread from the portal of entry to regional lymph nodes. This appears to be due to specific interactions between Tat and Env spikes that form a novel virus en...
Entry of wt Tat in MDDCs in the presence of different Env molecules and block by anti-integrins antibodies. Clade B trimeric wt Env (twt Env), trimeric ΔV2 Env (tΔV2 Env), monomeric wt Env (mwt Env), or monomeric ΔV2 Env (mΔV2 Env) molecules or buffer were incubated with Tat and added to MDDCs pre-treated with anti-integrin mAbs or a control isotyp...
Structural model of the ΔV1-2 Env/Tat binary complex. Color code: Env: dark blue; Env V3-loop: light blue; Tat: yellow; Tat cysteine-rich region: orange; and Tat RGD segment: red. (A) panels: surface representation; (B) panels: cartoon representation. See experimental procedures for details.
(TIF)
Blockade of Tat/Env complex entry into MDDCs by anti-Tat antibodies. Trimeric ΔV2 Env was incubated with PBS, a pool of sera from six HIV uninfected healthy donors, the same pool of sera plus the anti-Tat 2A4.1 mAb, Tat, or Tat plus 2A4.1 mAb, and added to cells. Cells were then stained for intracellular Env and analyzed by flow cytometry. The perc...
Blockade of Tat/Env complex binding in PBL by anti-CD4 antibodies. PBLs were pre-incubated with buffer or an anti-CD4 mAb and then incubated with twt Env or with twt Env which had been pre-incubated with the indicated amounts of Tat. PBLs were then stained with an anti-gp120 mAb and analyzed by flow cytometry. The percentage of Env-binding cells is...
Wt Tat, but not cys22 Tat, transactivates HIV-1 LTR in TZM-bl cells. RLU in HIV-1 LTR expressing TZM-bl cells cultured in the presence of buffer, or 0.1, 1, 10 µM wt Tat or cys22 Tat.
(TIF)
Block of trimeric ΔV2 Env or Tat/ΔV2 Env entry in MDDCs by anti-DC-SIGN and anti-integrins antibodies. (A) MDDCs from two different donors were pre-incubated with different concentration of an anti-DC-SIGN mAb (20 or 50 µg/mL) or with a control isotype mAb and then 70 nM (donor 1) or 35 nM (donor 2) trimeric ΔV2 Env (SF162) were added for 10 min pr...
Env and Tat interacting residues according to modeling docking analyses. Upper panel: Env interacting residues in the five lowest energy solutions. Residues involved in interactions are indicated by boxes. Different box colors correspond to different solutions. Secondary structure elements are colored as follows: the ΔV1-2 gp120 inner domain of Env...
Vaccine protocol design and schedule of immunization of cynomolgus monkeys.
(DOCX)
Structures used as templates to model the structures of Tat and Env.
(DOC)
Parameters used to perform MD simulations on the V3 loop of the Env protein.
(DOC)
Parameters used to perform docking calculations.
(DOC)
Parameters used to perform docking calculations.
(DOC)
Structural Model of the ΔV1-2 Env/Tat/Integrin αvβ3 Ternary Complex. Color code: ΔV1-2 Env: violet; Tat: yellow; integrin αvβ3: cyan.
(TIF)
CD4+ T cell counts, plasma viral load and proviral DNA load in blood, inguinal lymph nodes and rectal mucosal tissues at 4 week after intrarectal challenge with 70 MID50 of SHIVSF162P4cy.
Treatment of human immunodeficiency virus (HIV)-infected women with the highly active antiretroviral therapy (HAART) has reduced the onset of uterine cervical intraepithelial neoplasia (CIN), and halted its progression to cervical carcinoma. We and others demonstrated that the HIV protease inhibitors (HIV-PIs) used in HAART can exert direct antitum...
Background: The development of a vaccine against HIV/AIDS capable of preventing virus infection has been hampered by the HIV envelope (Env) heterogeneity that makes it difficult to induce neutralizing antibodies against Env proteins from different HIV clades. Several studies have indicated that gp120 Env protein sequence tends to change considerabl...
Human immunodeficiency virus protease inhibitors (HIV-PIs), such as indinavir and saquinavir, have been shown to block angiogenesis and tumor cell invasion and to induce tumor cell apoptosis and growth arrest, respectively, both in vitro and in vivo. These findings have suggested that HIV-PIs or their analogues can be used as antitumor drugs. To th...
The redox state of the cysteine-rich region of the HIV Tat protein is known to play a crucial role in Tat biological activity. In this article, we show that Tat displays two alternative functional states depending on the presence of either one or three reduced sulphydryl groups in the cysteine-rich region, respectively. Using different approaches,...
The effects of the challenge dose and major histocompatibility complex (MHC) class IB alleles were analyzed in 112 Mauritian
cynomolgus monkeys vaccinated (n = 67) or not vaccinated (n = 45) with Tat and challenged with simian/human immunodeficiency virus (SHIV) 89.6Pcy243. In the controls, the challenge dose (10 to 20 50% monkey infectious doses [...
The native HIV-1 Tat protein was chosen as vaccine candidate for phase I clinical trials based on its role in the natural infection and AIDS pathogenesis, on the association of Tat-specific immune response with the asymptomatic stage as well as on its sequence conservation among HIV clades. A randomized, double blind, placebo-controlled phase I stu...
The HIV epidemic continues to represent one of the major problems worldwide, particularly in the Asia and Sub-Saharan regions of the world, with social and economical devastating effects. Although antiretroviral drugs have had a dramatically beneficial impact on HIV-infected individuals that have access to treatment, it has had a negligible impact...
The native HIV-1 Tat protein was chosen as vaccine candidate for phase I clinical trials in both uninfected (ClinicalTrials.gov identifier: NCT00529698) and infected volunteers (ClinicalTrials.gov identifier: NCT00505401). The rationale was based on the role of Tat in the natural infection and AIDS pathogenesis, on the association of Tat-specific i...
Tat is an early regulatory protein that plays a major role in human HIV-1 replication and AIDS pathogenesis, and therefore, it represents a key target for the host immune response. In natural infection, however, Abs against Tat are produced only by a small fraction (approximately 20%) of asymptomatic individuals and are rarely seen in progressors,...
A randomized, double blind, placebo-controlled phase I vaccine trial based on the native Tat protein was conducted in HIV-infected asymptomatic individuals. The vaccine was administered five times subcute with alum or intradermally without adjuvant at 7.5microg, 15microg or 30microg doses, respectively. The Tat vaccine was well tolerated both local...
HIV protease inhibitors have been shown to exert antiangiogenic and antitumor actions independently from their antiretroviral effect. Based on these studies, HIV-seronegative patients with classic Kaposi's sarcoma were treated with indinavir and followed for clinical evolution, drug pharmacokinetics and Kaposi's sarcoma biomarkers. A favorable clin...
The native HIV-1 Tat protein was chosen as a vaccine candidate based on its key role in the virus life cycle and on the correlation of Tat-specific immune responses with the asymptomatic stage and lower disease progression rates, but also due to its sequence conservation amongst the various HIV clades as well as the adjuvant effects on dendritic ce...
Primary effusion lymphomas (PELs) are invariably infected by the human herpesvirus 8 (HHV8)that is present in most PEL cells as latent virus but replicates in a subset of permissive cells to produce infectious progeny. Here we show that productively infected PEL cells release C-type retrovirus-like particles encoding an Mn++-dependent RT activity,...
Primary effusion lymphoma (PEL) is a peculiar B-cell lymphoma characterized by infection by human herpesvirus type-8/Kaposi sarcoma-associated herpesvirus (HHV-8/KSHV) and by preferential growth in the serous body cavities. Histogenetic studies have suggested that PEL originates from B cells at a late stage of differentiation. In this study, we hav...
The "natural killer" (NK) cells preferentially kill targets lacking surface major histocompatibility complex class I (MHC-I) molecule expression. NK cells recognize these targets through membrane receptors, which can trigger activating or inhibitory signals for killing. Several tumors or virus-infected cells downregulate MHC-I expression as a mecha...
17094
Background: Our aim was to evaluate the activity of chemotherapy (CT) and indinavir, a protease inhibitor affecting matrix metalloproteases (mmps) of tumors, according to in-vitro studies (Sgadari, Nat Med 2002), in NSCLC patients (pts). Methods: All consecutive pts with NSCLC, IIIB and IV, underwent a platin-gemcitabine treatment. All pts wi...
14640
It is well known that during IL-2 administration a complex activation of the cytokine network is on going, but few data are available about the effect of this activation on angiogenesis. In our Institution all patients with metastatic RCC undergo to the following schedule of IL-2 infusion: IL-2 10 MIU continuous infusion (ci) 5/7 days, one we...
The human herpesvirus 8 (HHV-8) is a gamma herpesvirus with oncogenic potential which establishes a chronic infection that is normally controlled by the immune system of healthy individuals. In particular, CTL responses seem to play a key role in control of the infection. In this study, we characterized epitope-specific CTL responses in healthy HHV...
Primary effusion lymphomas (PELs) are invariably infected by human herpesvirus type 8 (HHV8) and often co-infected by Epstein-Barr virus (EBV). We found that expression of major histocompatibility complex class I (MHC-I) surface molecules was significantly decreased in PEL cells when compared with HHV8 negative lymphomas, irrespective of EBV infect...
Primary effusion lymphomas (PELs) are invariably infected by human herpesvirus type 8 (HHV8) and often co-infected by Epstein–Barr virus (EBV). We found that expression of major histocompatibility complex class I (MHC-I) surface molecules was significantly decreased in PEL cells when compared with HHV8 negative lymphomas, irrespective of EBV infect...
Infection by human immunodeficiency virus (HIV) is associated with an increased risk of certain tumours, particularly Kaposi's sarcoma, non-Hodgkin's lymphomas and cervical cancer. However, the incidence of these tumours in HIV-infected patients has decreased significantly since the widespread use of highly active antiretroviral therapy (HAART). Th...
This chapter reviews data showing that Fibroblast Growth Factors (FGF) are a family of related factors playing fundamental roles in several biological processes involving tissue remodeling such as embryonic development, angiogenesis, wound healing, nerve regeneration, chronic inflammation, and cancer. These processes are dependent on several biolog...
HIV protease inhibitors are antiretroviral drugs that block the enzyme required for production of infectious viral particles. Although these agents have been designed to selectively bind to the catalytic site of HIV protease, evidence indicates that other cellular and microbial enzymes and pathways are also affected. It has been reported that patie...
Kaposi's sarcoma (KS) develops more frequently in human immunodeficiency virus type 1 (HIV-1)-infected patients. In this study, we report that molecules released by CD8(+)CD28(-) T lymphocytes from HIV-1-infected patients promote endothelial-cell (EC) growth and induce ECs to acquire spindle cell morphology and upregulation of intercellular adhesio...
A reduced incidence and regression of Kaposi's sarcoma (KS) and other tumours has been reported in Acquired Immune Deficiency Syndrome (AIDS) patients treated with antiretroviral combination therapies containing Human Immunodeficiency Virus (HIV) protease inhibitors (PIs) such as indinavir or saquinavir. Indeed, evidence indicates that although PIs...
A reduced incidence or the regression of Kaposi's sarcoma (KS) has been described in HIV-infected patients treated with HIV-protease inhibitors (PI). We have recently demonstrated that PI block the angiogenesis and the development of KS lesions induced experimentally in vivo by the inoculation of angiogenic factors or human primary KS cells. These...
Kaposi's sarcoma (KS) is an angioproliferative disease of multifactorial origin arising in different clinic-epidemiologic forms, which show the same histopathological features. It generally starts as a hyperplastic reactive-inflammatory and angiogenic process, which may evolve into monomorphic nodules of KS cells that can be clonal (late-stage lesi...
Kaposi's sarcoma (KS) develops upon reactivation of human herpesvirus 8 (HHV8) infection and virus dissemination to blood and tissue cells, including endothelial and KS spindle cells where the virus is mostly present in a latent form. However, this may likely require the presence of compromised host immune responses and/or the evasion of infected c...
Kaposi's sarcoma (KS) is an angioproliferative disease of multifactorial origin arising in different clinic-epidemiologic forms, which show the same histopathological features. It generally starts as a hyperplastic reactive-inflammatory and angiogenic process, which may evolve into monomorphic nodules of KS cells that can be clonal (late-stage lesi...
The combination of interleukin 2 (IL-2) and antiretroviral therapy (ART) represents an emerging strategy in the treatment of patients infected with HIV. Aside from its immunomodulatory role, however, IL-2 may induce replication of human herpesvirus 8 (HHV-8)/Kaposi sarcoma (KS)-associated herpesvirus. We retrospectively evaluated HHV-8 plasma virem...
The human herpesvirus 8 (HHV-8) is a human gamma2-herpesvirus that is implicated in the development of Kaposi's sarcoma (KS), primary effusion lymphoma and Castelman's disease. Since the responses of cytotoxic T lymphocytes (CTL) play a key role in the control of herpesvirus infection, it is important to identify and to characterize the CTL target...
Treatment with HIV-1 protease inhibitors (PI) is associated with a reduced incidence or regression of Kaposi sarcoma (KS). Here we show that systemic administration of the PIs indinavir or saquinavir to nude mice blocks the development and induces regression of angioproliferative KS-like lesions promoted by primary human KS cells, basic fibroblast...
A human immunodeficiency virus—negative woman with severe classic Kaposi's sarcoma, idiopathic leukopenia, and massive spread
of human herpesvirus 8 (HHV-8) in circulating cells showed stable disease remission in response to systemic interferon-α treatment
that was accompanied by increased CD3+ and CD4+ T cell numbers and complete clearance of HHV-...
To determine whether the incidence of HHV-8/KSHV infection and the risk of developing KS among organ transplant recipients differ by type of organ transplanted, we calculated the rate of HHV-8/KSHV seroconversion and the risk of developing KS among renal and liver transplant recipients.
The study population consisted of renal and liver transplant r...
We studied residents of remote villages and the capital (Port Moresby) of Papua New Guinea to determine the distribution of human herpesvirus-8 (HHV-8) infection. Our data suggest that HHV-8 has been endemic on the island for a long time and that the epidemiologic pattern of HHV-8 is more similar to that of herpes simplex virus-2 than hepatitis C v...
Inflammatory cytokines (IC) activate endothelial cell adhesiveness for monocytes and inhibit endothelial cell growth. Here we report the identification of the human guanylate binding protein-1 (GBP-1) as the key and specific mediator of the anti-proliferative effect of IC on endothelial cells. GBP-1 expression was induced by IC, downregulated by an...
Previous studies indicated that the Tat protein of human immunodeficiency virus type-1 (HIV-1) is a progression factor for Kaposi's sarcoma (KS). Specifically, extracellular Tat cooperates with basic fibroblast growth factor (bFGF) in promoting KS and endothelial cell growth and locomotion and in inducing KS-like lesions in vivo. Here we show that...
Human herpes virus type 8 (HHV8) is the major determinant of Kaposi''s sarcoma (KS), a neoplasm with wide geographic variations in incidence rates. To assess the prevalence of HHV8 infection among populations with differing rates of KS, we used sera from 1402 persons (Central Africa: Cameroon, n = 293, age range: 5–40; eastern Africa: Uganda, n = 3...
A multicentre study was undertaken to define novel assays with increased inter-assay concordance, sensitivity, specificity and predictive value for serological diagnosis of human herpesvirus type 8 (HHV-8) infection. A total of 562 sera from European and Ugandan human immunodeficiency virus (HIV)-infected or uninfected individuals with or without K...
Human herpesvirus 8 (HHV-8) is found in immunoblastic B cells of patients with multicentric Castleman's disease (MCD) and, predominantly in a latent form, in primary effusion lymphoma (PEL) cells and Kaposi's sarcoma (KS) spindle cells. Recent studies have shown that upon reactivation, HHV-8 expresses factors that downregulate major histocompatibil...
Kaposi's sarcoma (KS) is an angioproliferative disease occurring in several different clinical-epidemiological forms that, however, share the same histological traits and are all associated with infection by the human herpesvirus 8 (HHV8). KS initiates in a context of immune dysregulation characterised by CD8+ T cell activation and the production o...
Kaposi's sarcoma (KS) develops through discrete inflammatory-angiogenic stages of polyclonal nature (early-stage lesions) to monomorphic nodules of spindle-shaped cells that can be clonal (late-stage lesions) and resemble true sarcomas. Molecular and epidemiological studies indicate that development of KS is tightly associated with infection by the...
