Sexually Transmitted Diseases (4th edition) (IV)
I was not super impressed with the coverage in part 3, although there was a lot of interesting stuff as well. However the level of coverage and amount of detail included is high in part four and five. There were a lot of details which evaded me in some of the recent chapters, but I also learned a great deal. There’s quite a lot of coverage of various ‘related topics’ (microbiology, biochemistry, immunology, oncology) in the parts of the book I’ve read recently, and like many other medical texts this book will help you realize that many things you in your mind had thought of as unrelated actually are connected in various interesting ways. It’s worth noting that given how many aspects of these things the book covers (again, 2000+ pages…) you actually get to know a lot of stuff about a lot of other things besides just ‘classic STDs’. It turns out that in Jamaica and Trinidad, over 70% of all lymphoid malignancies are attributable to exposure to a specific herpes virus most people probably haven’t heard about, HTLV-1 (prevalence is also high in other parts of the world, e.g. southern Japan). I didn’t expect to learn this from a book about sexually transmitted diseases, but there we are.
I hope that I’ve picked out stuff from this part of the coverage which is also intelligible to people who didn’t read the 95+% of those chapters I didn’t quote (I always like feedback on such aspects).
“At the simplest level, infection of a cell by a virus or bacterium may lead to cell death. In the case of viruses, specific disease syndromes may be caused by destruction of certain subsets of cells that express essential differentiated functions. A classic example of this is the development of the AIDS following HIV-1 mediated depletion of the CD4 lymphocyte population. Virus-induced cell death may result from one or more specific mechanisms. Many viruses express specific proteins that have as their major function the induction of a blockade in normal host cell metabolism (cellular translation and transcription) such that the metabolic machinery of the cell is subverted preferentially to viral replication. For obvious reasons, the expression of such proteins is usually highly toxic to the cell. Cellular destruction or “direct cytopathic effect” is considered responsible for the disease manifestations of many lytic viruses, including, for example, HSV and poliovirus. On the other hand, many cells may respond to the presence of an invading virus by the induction of apoptosis and the initiation of programmed cell death. Some viruses appear to have evolved mechanisms to prevent or delay apoptosis, thus potentially prolonging productive infection and maximizing replication. For example, HSV-1 infection induces apoptosis at multiple metabolic checkpoints but has also evolved mechanisms to block apoptosis at each point.28 Importantly, the inhibition of apoptosis by HSV-1 also prevents apoptosis induced by virus-specific cytotoxic T lymphocytes, thereby conferring on the infected cell a certain measure of resistance to the host’s cell-mediated immune responses.29
However, many viruses are not intrinsically cytopathic. HBV is a prime example, as many infected HBsAg carriers are asymptomatic and without overt evidence of active liver disease. Despite this, such carriers may be very infectious […] The presence or absence of liver disease is largely determined by the T-cell response to the virus.30 Thus, chronic hepatitis B results from a relatively vigorous but unsuccessful attempt on the part of the host to eliminate the infection. […] chronic liver inflammation and the occurrence of hepatocellular carcinoma reflect the immune response to the virus, rather than specific virus effects. Similar indirect mechanisms may contribute to the progressive immune destruction of infected CD4-positive lymphocytes in patients with HIV-1 infection.
Some bacterial disease processes may also be caused largely to immunopathologic responses. For instance, there is substantial evidence that complications of genital chlamydia infections (salpingitis, Reiter’s syndrome) are correlated with and may be owing to stimulation of antibodies against a heatshock protein (hsp60).33,34 […] In contrast, gonococcal tissue damage appears to be caused by the direct toxic effects of lipid A and peptidoglycan fragments”
“Some viruses are capable of altering differentiated cellular functions, resulting in the production of disease by mechanisms that do not exist among bacteria. A prime example is the altered cellular growth that follows infections by molluscum contagiosum virus (MCV) […]. A more extreme example is the proliferation of epithelial cells that is induced by infection with HPVs. HPV-related epithelial malignancies and cellular transformation are related to the expression of two specific HPV proteins, the E6 and E7 oncoproteins, by high-risk HPV subtypes.22 These proteins interact with p53 and pRb, both promoting cellular proliferation and cell survival. Oncogenic transformation is usually associated with high-level expression of E7 from integrated HPV DNA. The Kaposi’s sarcoma-associated herpes virus (KSHV) also expresses a number of proteins that mimic important host regulators of cellular proliferation and survival […] Expression of these proteins may result in deregulation of cell growth, with changes in the cellular morphology and/or acquisition of the ability of the cells to form colonies in soft agar, changes that are indicative of transformation.
On the other hand, hepatocellular cancers occurring in the context of chronic viral hepatitis are likely to have an alternative explanation. Although it is possible that integration of HBV DNA may be responsible for altered cellular growth control in some hepatitis B-associated cases, liver cancer in this setting may be primarily immunopathogenic.30,32 Chronic inflammation accompanied by oxidative stress and cellular DNA damage are likely to pla[y] important roles.”
“The human immunodeficiency viruses (HIV-1 and HIV-2) and the simian immunodeficiency viruses (SIV) (with a subscript indicating the species of origin) are members of the lentivirus genus of the Retroviridae family, commonly called retroviruses. […] Retroviruses are divided into two subfamilies: Orthoretrovirinae and Spumaretrovirinae […] The spumaretroviruses have distinctive features of their replication cycle that require this more distant classification. They have been isolated from primates, but not humans, and are not associated with any known disease. The orthoretroviruses are divided into six genera and represent viruses that infect snakes, fish, birds, and mammals. […] Human infections occur with viruses from two of these genera. The Deltaretrovirus genus includes human T-cell leukemia virus type I (HTLV-I), the causative agent of adult T-cell leukemia,5, 6, 7 and human T-cell leukemia virus type II (HTLV-II), which is not known to be associated with any disease syndrome. HTLV-I is also associated with another syndrome called HTLV-associated myelopathy (HAM). HTLV-I and HTLV-II are related to viruses found in primates and more distantly related to bovine leukemia virus. The lentivirus genus includes HIV-18 and HIV-29 as well as viruses found in a variety of mammals ranging from primates to sheep. Viruses within these different genera vary widely in the diseases they cause and the mechanisms of disease induction, in contrast to the many common features of their replication cycle. […] In its DNA form the viral genome is inserted into the host genome […]. This step in the virus life cycle has important implications for several features of virus-host interactions. For example, viral DNA that integrates into the genome of a cell but is not expressed becomes silently carried in the descendents of that cell. When this happens in a germline cell, or in the cell of an early embryo that becomes a germline cell, this copy of viral DNA becomes a linked physical part of the host genome, is present in every cell in the body, and is passed on to subsequent generations. Such a genetic element is called an endogenous retrovirus. Most of the elements that become fixed are defective, as there is probably a strong selective pressure against elements that can activate to produce infectious virus. Thus, they represent an archive within the host genome of previous waves of retroviral infections. In fact, the human genome carries a record of retroviral infections over the last 40 million years of primate evolution. These are viruses that we do not recognize as active in the human population at present but are represented by 110,000 genomic inserts of gammaretroviruses, 10,000 inserts of betaretroviruses, and 80,000 inserts of a genus that may be distantly related to spumaretroviruses or may represent an uncharacterized lineage.10 Most of these elements contain large deletions; however, if these deletions had been retained, our genomes would be 40% endogenous retroviruses by mass and outnumber our normal genes 7 to 1.”
“Most histories of retroviruses start with the dramatic discovery by Peyton Rous in 1911 that a virus, Rous sarcoma virus (RSV), could cause cancer. […] The isolation of other tumor-causing retroviruses followed and in time it became apparent that there were two broad classes of agents: one class of viruses caused cancer after a long latency period […], while the other class caused tumors that appeared rapidly […]. We now know that the acutely transforming retroviruses carry a cell-derived oncogene that is responsible for the transforming activity,14 while the slowly transforming retroviruses act by the chance integration of viral DNA near these cellular oncogenes in the host genome to induce their expression and promote tumor formation.15,16 Importantly, many of these same genes can be mutated or overexpressed in human cancers, and the proteins they encode are now the targets of new generations of specific antitumor therapies […] One can confidently surmise that the remnants of the beta- and gammaretroviruses littered in our genomes had such oncogenic effects when they were active. Ironically, for the active human retroviruses, HTLV-I causes tumors by a different but still poorly understood mechanism, and HIV is involved in tumor formation only indirectly through immune suppression. […] There are two fundamental differences between lentiviruses and most other retroviruses: Lentiviruses do not cause cancer [directly…] and they establish chronic infections that result in a long incubation period followed by a chronic symptomatic disease. The “slow” (lenti is Latin for slow), chronic nature of these viral infections was first appreciated for a disease of sheep called maedi-visna (maedi = labored breathing, visna = paralysis and wasting).”
“Using the current sequence diversity in the HIV-1 population, the 1959 sequence, and estimates of the rate of sequence change per year, it has been possible to suggest that the cross-species transmission event that gave rise to the M group of HIV-1 occurred early in the twentieth century.38 If we accept that SIVcpz [HIV in chimps…] has entered the human population three times in the last century (the three groups N,O, and M), then it follows that this virus likely has been transmitted to humans any number of times over the last 10,000 years. Only in the last century the human institutions of large cities and efficient transportation corridors have given these transmission events access to a human environment that could support an epidemic.”
“Over 100 herpesviruses have been identified, with at least eight infecting humans [I had no idea there were that many of them, and I had no clue some of the ones mentioned were actually herpes viruses…]. All human herpesviruses are well adapted to their natural host, being endemic in all human populations studied and carried by a significant fraction of persons in each population. The human herpesviruses include herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), and human herpesvirus 8 (HHV-8) or Kaposi’s sarcoma (KS)-associated herpesvirus. Disease caused by human herpesviruses tends to be relatively mild and self-limited in immunocompetent persons, although severe and quite unusual disease can be seen with immunosuppression. […] all herpesviruses share biologic traits. These include expression of a large number of viral enzymes, assembly of the nucleocapsid in the cell nucleus, cytopathic effects on the cell during productive infection, and ability to establish latent infections in an infected host.”
“Vaccine development poses great challenges in the case of herpesviruses because recovery from natural disease is not associated with elimination of virus and does not always protect against another episode of disease.
Live-attenuated, killed, and recombinant subunit herpesvirus vaccines have all been studied. Whole-virus vaccines have the advantage of exposing the immune system to all viral antigens. Live-attenuated vaccines have tended to produce longer-lasting immunity than killed preparations. However, live-attenuated herpesvirus vaccines may be capable of establishing latent infections. The risks are not clear and there is concern that vaccine recipients who subsequently become immunosuppressed may develop disease caused by reactivated virus. Two avirulent HSV strains have been shown to generate lethal recombinants in mice.127 Thus, recombination between an attenuated vaccine strain and a superinfecting wild-type strain could occur. Because several herpesviruses have been associated with malignancies in humans, the long-term safety of any live-attenuated vaccine needs careful study.”
“In the most recent data from NHANES, the prevalence of HSV-1 appears to have fallen slightly from 62% in the years 1988-1994 to 57.7% in the years 1999-2004 in the general population.30 In Western Europe, the prevalence of HSV-1 infection in young adults remains 10-20% higher than that in the United States.31 In STD clinics in the United States, about 60% of attendees have HSV-1 antibodies. In Asia and Africa, HSV-1 infection remains almost universal […] The cumulative lifetime incidence of HSV-2 reaches 25% in white women, 20% in white men, 80% in African American women and 60% in African American men […] Transmission of HSV between sexual partners has been addressed most often in prospective studies of serologically discordant couples, i.e., in couples in whom one partner has and the other does not have HSV-2. Longitudinal studies of such couples have shown that the transmission rate varies from 3% to 12% per year. […] Unlike other STDs, persons usually acquire genital HSV-1 and genital HSV-2 in the context of a steady rather than casual relationship.91 Women have higher rates of acquisition than men; in one study the attack rate among seronegative women approached 30% per year.88 […] Subclinical or asymptomatic viral shedding is an important aspect of the clinical and epidemiologic understanding of genital herpes, as most episodes of sexual and vertical transmission appear to occur during such shedding. […] the risk of HSV transmission is likely similar regardless of the presence of lesions, supporting the epidemiologic observation that most HSV is acquired from asymptomatic partners. […] Subclinical HSV reactivation is highest in the first year after acquisition of infection. During this time period, HSV can be detected from genital sites by PCR on a mean of 25-30% of days […]. This is about 1.5 times higher than patients sampled later in their disease course.”
“The major morbidity of recurrent genital herpes is its frequent reactivation rate. Most likely, all HSV-2 seropositive persons reactivate HSV-2 in the genital region. Moreover, because of the extensive area enervated by the sacral nerve root ganglia, reactivation of HSV-2 is widespread over a large anatomic area.
A prospective study of 457 patients with documented first-episode genital herpes infection has shown that 90% of patients with genital HSV-2 developed recurrences in the first 12 months of infection.93 The median recurrence rate was 0.33 recurrences/month. Most patients experienced multiple clinical reactivations. After primary HSV-2 infection, 38% of patients had at least 6 recurrences and 20% had more than 10 recurrences in the first year of infection. Men had slightly more frequent recurrences than women, median 5 per year compared with 4 recurrences per year [it’s important to note that the recurrence rate is substantial even in patients on suppressive therapy: “About 25% of persons on suppressive therapy will develop a breakthrough recurrence each 3-month period”] […] Recently, long-term cohort studies indicate that the frequency of symptomatic recurrences gradually decreases over time. In the initial years of infection, reported recurrence rate decreases by a median of 1 recurrence per year. […] subclinical shedding episodes account for one-third to one-half of the total episodes of HSV reactivation as measured by viral isolation and for 50-75% of reactivations as measured by PCR. […] Rather than regarding HSV-2 as a predominantly silent infection with occasional clinical outbreaks with marked viral shedding, HSV is a dynamic infection, with very frequent reactivation, mostly subclinical, and active effort on the part of the immune system of the host is required to control mucosal viral replication. […] Immunocompromised patients have frequent and prolonged mucocutaneous HSV infections.226, 227, 228 Over 70% of renal and bone marrow transplant recipients who have serologic evidence of HSV infection reactivate HSV infection clinically within the first month after transplantation […] Recurrent genital herpes in immunosuppressed patients often results in the development of large numbers of vesicles which coalesce into extensive deep, often necrotic, ulcerative lesions.228 […] about 70% of HIV-infected persons in the developed world and 95% in the developing world have HSV-2 antibody. […] The epidemiologic interactions between HIV and HSV-2 have led to calculation of potential population-level impact of these intersecting epidemics. […] The population attributable risk will depend on the prevalence of HSV-2 in the population at risk; at 50% HSV-2 prevalence, common among MSM [Males who have Sex with Males, US], or African Americans in the United States, or general population in sub-Saharan Africa, 35% of HIV infections will be attributable to HSV-2. […] the risk of transmitting HSV [from the mother] to the neonate is 30-50% in women with newly acquired HSV [during the last part of the pregnancy] versus <1% in women with established infection.” [This is relevant not only because herpes sucks, but also because it sucks even more when a newborn child gets it].
“More than 50% of individuals in most populations throughout the world demonstrate serological evidence of prior CMV infection.6 The coevolution with and adaptation to its human host over millions of years may account for the observation that in most cases, CMV infection causes few if any symptoms.5 However, in immunocompromised individuals, primary infection or reactivation of latent virus can be life-threatening. As well, congenital infections are common and can result in serious lifelong sequelae. […] Although CMV does not typically come to medical attention as a result of genital tract lesions or disease, it can be transmitted sexually and has important consequences for the sexually active, child-bearing population. […] As with many viruses that cause chronic infection, CMV seems to have coevolved with humans to a balanced state in which the virus persists but generally causes little clinical illness. The host’s innate and adaptive immune responses are usually successful at limiting CMV infection as is evident by the clear association of immune system dysfunction with CMV disease. In the absence of prophylactic antiviral treatment, CMV often reactivates in seropositive individuals who undergo hematopoietic stem cell transplantation (HSCT).41 Immunosuppression resulting from drugs used to treat cancer and autoimmune disorders, and from impaired T-cell function that occurs with advanced AIDS, is also associated with reactivation of CMV. […] The development of primary CMV infection has been noted in up to 79% of liver transplants and 58% of kidney or heart transplants in which the donor is seropositive and the recipient is seronegative.134,135 In the setting of HSCT, several studies have documented that CMV seropositivity of the recipient results in significantly increased overall posttransplant mortality compared to CMV seronegative recipients with a seronegative donor.136 When the recipient is CMV seronegative, overall mortality is increased when the donor is seropositive compared to the situation where the donor is seronegative.137 […] the transplant recipient is at particularly high risk of CMV reactivation during periods of potent immunosuppression that accompany graft rejection or graft-versus-host disease.”
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