Rab Proteins: Insights into Intracellular Trafficking in Endometrium.

Rab proteins belong to the Ras superfamily of small monomeric GTPases. These G proteins are the main controllers of vesicular transport in every tissue, among them, the endometrium. They are in charge of to the functional subcellular compartmentalization and cargo transport between organelles and the plasma membrane. In turn, intracellular trafficking contributes to endometrial changes during the menstrual cycle, secretion to the uterine fluid, and trophoblast implantation; however, few reports analyze the role of Rab proteins in the uterus. In general, Rab proteins control the release of cytokines, growth factors, enzymes, hormones, cell adhesion molecules, and mucus. Further, the secretion of multiple compounds into the uterine cavity is required for successful implantation. Therefore, alterations in Rab-controlled intracellular transport likely impair secretory processes to the uterine fluid that may correlate with abnormal endometrial development and failed reproductive outcomes. Overall, they could explain recurrent miscarriages, female infertility, and/or assisted reproductive failure. Interestingly, estrogen (E2) and progesterone (P) regulate gene expression of Rab proteins involved in secretory pathways. This review aims to gather information regarding the role of Rab proteins and intracellular trafficking in the endometrium during the different menstrual phases, and in the generation of a receptive stage for embryo implantation, modulated by E2 and P. This knowledge might be useful for the development of novel reproductive therapies that overcome low implantation rates of assisted reproductive procedures.

COVID-19 and human spermatozoa-Potential risks for infertility and sexual transmission?

As COVID-19 infections wreak havoc across the globe, attention has rightly been focused on the vital organ systems (lung, kidney and heart) that are vulnerable to viral attack and contribute to the acute pathology associated with this disease. However, we should not lose sight of the fact that COVID-19 will attack any cell type in the body expressing ACE2 - including human spermatozoa. These cells possess the entire repertoire of receptors (AT1R, AT2R, MAS) and ligand processing enzymes (ACE1 and ACE2) needed to support the angiotensin signalling cascade. The latter not only provides COVID-19 with a foothold on the sperm surface but may also promote integration, given the additional presence of a range of proteases (TMPRSS2, TMPRSS11B, TMPRSS12, furin) capable of promoting viral fusion. This article reviews the roles played by these various cellular constituents in maintaining the vitality of human spermatozoa and their competence for fertilization. The reproductive consequences of a viral attack on these systems, in terms of fertility and the risk of sexual transmission, are currently unknown. However, we should be alive to the possibility that there may be reproductive consequences of COVID-19 infection in young males that go beyond their capacity to survive a viral attack.

Semen-derived amyloidogenic peptides-Key players of HIV infection.

Misfolding and amyloid aggregation of intrinsically disordered proteins (IDPs) are implicated in a variety of diseases. Studies have shown that membrane plays important roles on the formation of intermediate structures of IDPs that can initiate (and/or speed-up) amyloid aggregation to form fibers. The process of amyloid aggregation also disrupts membrane to cause cell death in amyloid diseases like Alzheimer's disease and type-2 diabetes. On the other hand, recent studies reported the membrane fusion properties of amyloid fibers. Remarkably, amyloid-fibril formation by short peptide fragments of highly abundant prostatic acidic-phosphatase (PAP) in human semen and are capable of boosting the rate of HIV infection up to 400,000-fold during sexual contact. Unlike the least toxic fully matured fibers of most amyloid proteins, the semen-derived enhancer of virus infection (SEVI) amyloid-fibrils of PAP peptide fragments are highly potent in rendering the maximum rate of HIV infection. This unusual property of amyloid fibers has witnessed increasing number of studies on the biophysical aspects of fiber formation and fiber-membrane interactions. NMR studies have reported a highly disordered partial helical structure in a membrane environment for the intrinsically disordered PAP peptide that promotes the fusion of the viral membrane with that of host cells. The purpose of this review article is to unify and integrate biophysical and immunological research reported in the previous studies on SEVI. Specifically, amyloid aggregation, dramatic HIV infection enhancing properties, membrane fusion properties, high resolution NMR structure, and approaches to eliminate the enhancement of HIV infection of SEVI peptides are discussed.

A novel role for APOBEC3: susceptibility to sexual transmission of murine acquired immunodeficiency virus (mAIDS) is aggravated in APOBEC3 deficient mice.

BACKGROUND: APOBEC3 proteins are host factors that restrict infection by retroviruses like HIV, MMTV, and MLV and are variably expressed in hematopoietic and non-hematopoietic cells, such as macrophages, lymphocytes, dendritic, and epithelia cells. Previously, we showed that APOBEC3 expressed in mammary epithelia cells function to limit milk-borne transmission of the beta-retrovirus, mouse mammary tumor virus. In this present study, we used APOBEC3 knockout mice and their wild type counterpart to query the role of APOBEC3 in sexual transmission of LP-BM5 MLV - the etiological agent of murine AIDs (mAIDs). RESULTS: We show that mouse APOBEC3 is expressed in murine genital tract tissues and gametes and that genital tract tissue of APOBEC3-deficient mice are more susceptible to infection by LP-BM5 virus. APOBEC3 expressed in genital tract tissues most likely plays a role in decreasing virus transmission via the sexual route, since mice deficient in APOBEC3 gene have higher genitalia and seminal plasma virus load and sexually transmit the virus more efficiently to their partners compared to APOBEC3+ mice. Moreover, we show that female mice sexually infected with LP-BM5 virus transmit the virus to their off-spring in APOBEC3-dependent manner. CONCLUSION: Our data indicate that genital tissue intrinsic APOBEC3 restricts genital tract infection and limits sexual transmission of LP-BM5 virus.

Semen-derived amyloid fibrils drastically enhance HIV infection.

Sexual intercourse is the major route of HIV transmission. To identify endogenous factors that affect the efficiency of sexual viral transmission, we screened a complex peptide/protein library derived from human semen. We show that naturally occurring fragments of the abundant semen marker prostatic acidic phosphatase (PAP) form amyloid fibrils. These fibrils, termed Semen-derived Enhancer of Virus Infection (SEVI), capture HIV virions and promote their attachment to target cells, thereby enhancing the infectious virus titer by several orders of magnitude. Physiological concentrations of SEVI amplified HIV infection of T cells, macrophages, ex vivo human tonsillar tissues, and transgenic rats in vivo, as well as trans-HIV infection of T cells by dendritic or epithelial cells. Amyloidogenic PAP fragments are abundant in seminal fluid and boost semen-mediated enhancement of HIV infection. Thus, they may play an important role in sexual transmission of HIV and could represent new targets for its prevention.

Epidemiología de la infección por el virus del papiloma humano y del cáncer de cérvix / Epidemiology of human papilloma virus infection and cervical cancer

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Porphyrin abnormalities in acquired immunodeficiency syndrome.

OBJECTIVE: To examine prospectively porphyrin metabolism in a human immunodeficiency virus (HIV)-positive population. SETTING: Specialist referral unit at the Department of Genitourinary Medicine, St James's Hospital, Dublin, Ireland. PATIENTS: Twenty-eight men and 5 women (age range, 18-35 years). Twenty-nine were current or previous intravenous drug abusers. Four were thought to have sexually acquired HIV infection. All had a history of acquired immunodeficiency syndrome-defining illnesses. The patients were selected as a consecutive sample from the inpatient department. Eligibility criteria were cooperation with urine and stool collection and confirmed HIV seropositivity. The patients were matched to 2 groups: 1 with normal results of porphyrin studies and the other with abnormal findings from porphyrin studies. INTERVENTION: None. MAIN OUTCOME MEASURES: Plasma, urine, and stool porphyrin excretion patterns. RESULTS: Of the 33 patients in the study, 13 (40%) had increased urinary porphyrin excretion. All but 2 of these patients were seropositive for hepatitis C virus. No study patient had clinical evidence of porphyria. Four patients (12%), however, had urine and stool porphyrin excretion patterns that were classic for porphyria cutanea tarda. All 4 of these patients were hepatitis C virus-positive. Patients with porphyrinuria had a greater degree of immunosuppression (P = .002) than those with normal porphyrin metabolism, and they were more likely to be taking zidovudine (P = .009). CONCLUSIONS: Commonly, porphyrin metabolism is abnormal in persons with established HIV infection. Hepatitis C may contribute to abnormal porphyrin metabolism. An unexpected number of patients studied had porphyrin excretion patterns that were characteristic of porphyria cutanea tarda, and all of these were hepatitis C virus-positive. A diagnosis of porphyria cutanea tarda, especially in a young patient, should prompt investigation for underlying HIV and hepatitis C virus infections. Dermatologists should be aware of the infectious risk associated with the vesicles and erosions in these patients. Porphyrin studies should be performed in any patient with HIV and photosensitivity.