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HIV is a global pandemic. Worldwide, it is claimed there are more than 33.3 (31.4-35.3) million people who live with HIV-1 and, to date, it is estimated that 25 million people have died from HIV-1. Only 5 years ago, the incidence rate of HIV-1 infection was 4.1 million and death from AIDS was 2.8 million. The primary mode of transmission is through heterosexual transmission; this equates to 85% of all HIV-1 infections. Although a global pandemic, the highest rates of new HIV-1 infection still remain in Southern Africa. Drug abuse also contributes to HIV-1 transmission which amounts to a third of HIV-1 infections; this is estimated to be 8.8 million in central and southeast Asia and Eastern Europe. It is believed that increasing HIV-1 infections in women is the major feature of the HIV pandemic over the last 10 years; highlighting vertical transmission during pregnancy as a major implication in HIV incidence. Adults aged under 25 years equate to a quarter of all new HIV-1 infections, while infection rates are higher in females than males; approximately 3-6 times. There are many aspects to HIV-1 modes of transmission including coexisting sexual partners, change in partners, sexual practices, vertical transmission, socioeconomic and reasons.
There are a multitude of aspects to the pathogenesis of HIV-1 infection that effects the duration of infection, and target cell type and cell activation affects the outcome. HIV-1 target T-helper cells (CD4+). These are responsible for activating cytotoxic T-cells (CD8+) and induce class switching in antibody producing B-cells. As cytotoxic T-cells are responsible to target viruses, HIV-1 infected individuals are prone to viral infections. Conversely, B-cells produce antibodies that are essential in microbial infections; therefore HIV-1 infected individuals are susceptible to microbial infections.
During the early stage, the virus gains entry to target cells without causing damage. This may result in the stimulation of intracellular signals that, in turn, initiates viral replication. On the HIV-1 virus, there are two molecules present including a transmembrane protein (gp41) and an external glycoprotein (gp120) as shown in figure 1. The entry process firstly involves the binding of the gp120 to the CD4+ receptor. Irreversible conformation changes occur during subsequent interactions between the virus and chemokine co-receptors. Through pore formation, fusion of the virus and the CD4+ cell takes place; this results in the release of the viral core into the target cell cytoplasm. Following this, the core becomes disassembled whereby the viral genome can then be reversed transcribed into DNA; this is achieved by the reverse transcriptase of the virus.
Figure 1: the life cycle of the HIV-1 virus
During the later steps, both virus and host contribute to transcription leading to the production of viral particles. The viral particles are then transported close to the cell membrane to be assembled. There is no lysis of the host cell during viral egress from the cell; this is achieved through a process from the vesicular sorting pathway (ESCRT-I, II, III). This process results in the formation of endosomes that bud out of cells. The virions have characteristics of the producer cell as they have incorporated cytoplasmic molecules and cell surface lipid bilayer components. The phonotype of the virus can be determined by the host molecules that have been incorporated. This may have an affect on both the replication in subsequent infection cycles or immune activation of bystander cells may be mediated (Simon 2006). Although the symptoms of infection is lacking during the both early and chronic phase, the replication of the virus is dynamic during the course of HIV-1 infection. During a thirty minute period, half of the virus population in the plasma is replaced; this is due to the short half life of each single virion. During chronic HIV-1 infection, there may be more than 1010 viral particles produced per day. There are many proposals put forward to explain the different depletion mechanisms, however, the consensus for the cause of CD4+ cell reservoir depletion, remains in generalised immune activation.
The result of HIV-1 infection observes the gradual destruction in the population of both memory and naïve CD4+ T-cells, with the end stage of this infection leading to AIDS. Due to the reduction of CD4+ cells in an HIV-1 infected individual, they have an increased susceptibility to opportunistic infections including viral, microbial and fungal infections.
Molluscum contagiosum is a skin condition that result in wart-like skin lesions in the epidermal layer; histologically referred to as a acanthoma. The causative agent is the molluscum contagiosum virus (MCV). This virus belongs to the Poxviridae family and the type species of the genus Molluscipoxvirus.
In a recent case report by Legett et al., they presented a case of a 59 year old African American male. His history included receiving a kidney transplant three years earlier. As a result, he was placed on immunosuppressive medication to prevent graft rejection. His medication included tacrolimus, methylprednisolone, and mycophenolate mofetil. As he was immunosupressed, he was more susceptible to opportunistic infections. His symptoms included headaches, change in mental status, and difficulty walking; all within a 1-week period. He also presented with an enlarging plaque on his right cheek over a week period. Following a lumber puncture, they had found the patient to have cryptococcal meningitis. A biopsy was also taken; which revealed yeast-like organisms within the dermis, and also in histiocytes in a pauci inflammatory, foamy stroma. By using a mucicarmine stain, capsules were also observed. Cutaneous crytococcus was also made; secondary to the disseminated disease. They go on to discuss the course of treatment for the cutaneous lesions following the administration of the oral antifungals.
Cryptococcus neoformans is the causative agent of cutaneous cryprococcus. It is an encapsulated unicellular yeast which is ubiquitous in the environment. It replicates through budding. Cryptococcus neoformans are the only members of the cyptococcus genus which are pathogenic to humans. The cryptococcus species previously included two types; C. neoformans var. neoformans (serotypes A and D) and C. neoformans var. gattii (serotypes B and C). Now they have been reclassified so C. neoformans var. gatti is a distinct species, and also serotypes A and D were separated; C. neoformans var. grubii (serotype A) and C. neoformans var. neoformans (serotype D).
Another clinical manifestation of cryptococcus in HIV is typically cryptococcal meningitis. A case report by Chronister (2006) outlines a case whereby an HIV patient had presented with complaints of headache, neck pain and unsteady gait. A lumber puncture and subsequent testing revealed cryptococcal infection.
There are a number of fungal infections that HIV infected individuals are commonly susceptible to:
Candidosis - The majority of HIV infected individuals become infected during their illness with oropharyngeal candidosis (OPC) due to impaired cell-mediated immunity. The most common site of mucosal candidosis is the oropharynx. However, in more advance stages of HIV infection, it may occur in the oesophagus and the tracheobronchial tree. In HIV infected women, it is more likely to result in candidal vulvovaginosis (CVV). This may also be a useful indicator for immunodeficiency in a clinical setting. Candida intertrigo is more common than mucosal candidosis in a normal individual; this is uncommon in HIV individuals.
Dermatophytoses - The prevalence of the dermatophytic pathogens are the same in both HIV individuals and normal hosts. 90% of infections are caused by T. rubrum and there are only less than 10% of T. Mentagrophytes infections in adults. The epidermis and nails are infected with T. rubrum but does not cause a superficial infection of the scalp (tinea capitis).
Sporotrichosis - Rotting organic matter is the ideal environment for Sporotrix schenkii. Limited forms of cutaneous sporotrichosis results from percutaneous infection. However, this may become a disseminated infection of organs, lung and skin foci in an HIV infected individual.
Aspergillosis - Infection with aspergillus with HIV is relatively uncommon; occurring as a primary cutaneous infection, around venous catheters or as a disseminated infection.
Coccidioidomycosis - In advanced HIV infection, disseminated or latent pulmonary infection may occur.
Histoplasmosis - this is the leading cause of opportunistic infection in HIV, in endemic areas; causing disseminated histoplasmosis
Blastomycosis - pulmonary, disseminated or extrapulmonary infection may occur with Blastomyces dermatidis. However, it is limited to south-central and Midwest US states.
Penicilliosis - In countries including areas in China and Asia, Penicillium marneffei is one of the most frequent opportunistic infection in HIV patients.
The most AIDS-defining illness, in western countries, was Pneumocystis jiroveci pneumonia. Conversely, the most frequent life-threatening opportunistic infection in developing countries if TB, in individuals with HIV/AIDS. It is estimated that around 25 to 65% of HIV/AIDS are infected with TB. Globally, it has also been estimated that 11.5 million individuals had HIV and TB co-infection, by the end of the year 2000. The distribution of HIV and TB co-infected individuals equated to 70% of people in sub-Saharan Africa, 20% in South -East Asia and 4% in southern areas of the US. 13% of HIV related deaths are due to TB infection. It is estimated that half of the 5.1 million HIV individuals in India are co-infected with TB, and the incidence of active TB will develop in approximately 200,000 of co-infected individuals per year.
The intensity of immunosuppression that results from the HIV infection has a profound affect on the clinical presentation of TB/HIV co-infections. Pulmonary TB (PTB) is more frequent than extrapulmonary TB (EPTB) when the CD4+ count is greater than 200/mm3. Lobe infiltrates and cavitation are observed on radiographic findings in these patients, these are comparable findings to PTB infected individuals who are HIV negative. These patients are also frequently positive for acid-fast bacilli (AFB) from sputum smears. While CD4+ cells are depleted, it is more common for EPTB to develop. Disseminated infection is more frequent in HIV individuals with EPTB than those who are HIV negative. AFB sputum smears are rarely positive in more advanced HIV infections. It has been noted that with advanced immunosuppression, there are 10 to 20% of patients have normal chest radiographs, but they have TB isolated in sputum or bronchoalveolar lavage (BAL) samples. Abdominal TB, meningitis, pleural effusion, and extrathoracic lymphnode TB are common clinical findings of EPTB. Poor granuloma formation characterises the lymph node involvement and is accompanied with AFB, florid necrosis and neutrophil infiltration; this is commonly found in more advanced stages of HIV/AIDS. The TB causing pleural effusion in HIV negative individuals often spontaneously resolve. Conversely, in HIV positive patients, pleural effusion is more progressive and these individuals can remain culture-positive for M. tuberculosis. Because there is a reduction in the inflammatory response due to HIV infection, there is an abundance of mesothelial cells in the pleural fluid. Other clinical manifestations include TB meningitis, and severe weightloss when accompanied with diarrhoea.
Isoniazid and rifampicin are two anti-TB drugs to treat active TB infection. Both of these drugs are used as the 'first-line' treatment to TB. When TB becomes resistant to these two drugs, it is referred to as multi-drug resistant tuberculosis (MDR TB). MDR TB can develop into extensively drug resistant tuberculosis (XDR TB); The CDC defines XDR TB as 'TB which is resistant to isoniazid and rifampin, plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin).' Due to nature of resistance displayed by XDR TB, there are very little effective treatments left for XDR TB infected individuals. More over, HIV infected individuals who have a XDR TB co-infection have a high risk of death.
The CDC explains how drug resistance occurs in TB. They explain that it is the result of when drugs are either mismanaged or misused. The misuse includes poor patient compliance; i.e. the full course of treatment is not completed. Mismanagement of anti-TB drugs may include, incorrect dosage, incorrect drug combination, too short time period of treatment, or prescribing poorly quality of the drugs. An individual is also of high risk to developing MDR TB if they reside in areas where MDR TB is common or contact with an individual who has had MDR TB. These factors highlight a reason for increasing incidence of multi drug resistant TB infections.
Single mutations that result in amino acid substitutions to target proteins, are the mechanism of drug resistance in TB. For example, mutations in the katG-encoded catalase-peroxidase, allows resistance to isoniazid. The arabinogalactan component of the cell envelop of the mycobacterium is blocked with Ethambutol.