What are the later symptoms of HIV/AIDS?

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  Lack of energy
  Weight loss
  Frequent fevers and sweats
  A thick, whitish coating of the tongue or mouth (thrush) that is caused by a yeast infection and sometimes accompanied by a sore throat
  Severe or recurring vaginal yeast infections
  Chronic pelvic inflammatory disease or severe and frequent infections like herpes zoster
  Periods of extreme and unexplained fatigue that may be combined with headaches, lightheadedness, and/or dizziness
  Rapid loss of more than 10 pounds of weight that is not due to increased physical exercise or dieting
  Bruising more easily than normal
  Long-lasting bouts of diarrhoea
  Swelling or hardening of glands located in the throat, armpit, or groin
  Periods of continued, deep, dry coughing
  Increasing shortness of breath
  The appearance of discoloured or purplish growths on the skin or inside the mouth
  Unexplained bleeding from growths on the skin, from mucous membranes, or from any opening in the body
  Recurring or unusual skin rashes
  Severe numbness or pain in the hands or feet, the loss of muscle control and reflex, paralysis or loss of muscular strength
  An altered state of consciousness, personality change, or mental deterioration
  Children may grow slowly or fall sick frequently. HIV positive persons are also found to be more vulnerable to some cancers.

What Happens Inside the Body?

Once HIV enters the human body, it attaches itself to a White Blood Cell (WBC) called CD4. Also, called T4 cells, they are the main disease fighters of the body. Whenever there is an infection, CD4 cells lead the infection-fighting army of the body to protect it from falling sick. Damage of these cells, hence can affect a person's disease-fighting capability and general health. After making a foothold on the CD4 cell, the virus injects its RNA into the cell. The RNA then gets attached to the DNA of the host cell and thus becomes part of the cell's genetic material. It is a virtual takeover of the cell. Using the cell's division mechanism, the virus now replicates and churns out hundreds of thousands of its own copies. These cells then enter the blood stream, get attached to other CD4 cells and continue replicating. As a result, the number of the virus in the blood rises and that of the CD4 cells declines. Because of this process, immediately after infection, the viral load of an infected individual will be very high and the number of CD4, low. But, after a while, the body's immune system responds vigorously by producing more and more CD4 cells to fight the virus. Much of the virus gets removed from the blood. To fight the fast-replicating virus, as many as a billion CD4 cells are produced every day, but the virus too increases on a similar scale. The battle between the virus and the CD4 cells continues even as the infected person remains symptom-free. But after a few years, which can last up to a decade or even more, when the number of the virus in the body rises to very high levels, the body's immune mechanism finds it difficult to carry on with the battle. The balance shifts in favour of the virus and the person becomes more susceptible to various infections. These infections are called Opportunistic Infections because they swarm the body using the opportunity of its low immunity. At this stage, the number of CD4 cells per millilitre of blood (called CD4 Count), which ranges between 500 to 1,500 in a healthy individual, falls below 200. The Viral Load, the quantity of the virus in the blood, will be very high at this stage. Opportunistic infections are caused by bacteria, virus, fungi and parasites. Some of the common opportunistic infections that affect HIV positive persons are: Mycobacterium avium complex (MAC), Tuberculosis (TB), Salmonellosis, Bacillary Angiomatosis (all caused by bacteria); Cytomegalovirus (CMV), Viral hepatitis, Herpes, Human papillomavirus (HPV), Progressive multifocal leukoencephalopathy (PML) (caused by virus); Candidiasis, Cryptococcal meningitis (caused by fungus) and Pneumocystis Carinii pneumonia (PCP). Toxoplasmosis. Cryptosporidiosis (caused by parasites). HIV positive persons are also prone to cancers like Kaposi's sarcoma and lymphoma. The Center for Disease Control (CDC), Atlanta has listed a series of diseases as AIDS-defining. When these diseases appear, it is a sign that the infected individual has entered the later stage of HIV infection and has started developing AIDS. The progression of HIV positive persons into the AIDS stage is highly individual. Some people can reach the AIDS stage in about five years, while some remain disease free for more than a decade. Measurement of the viral load and the CD4 count helps a doctor in assessing an infected person's health condition.

What are the early symptoms of HIV infection?

Many people do not develop any symptoms when they first become infected with HIV. Some people, however, get a flu-like illness within three to six weeks after exposure to the virus. This illness, called Acute HIV Syndrome, may include fever, headache, tiredness, nausea, diarrhoea and enlarged lymph nodes (organs of the immune system that can be felt in the neck, armpits and groin). These symptoms usually disappear within a week to a month and are often mistaken for another viral infection.

During this period, the quantity of the virus in the body will be high and it spreads to different parts, particularly the lymphoid tissue. At this stage, the infected person is more likely to pass on the infection to others. The viral quantity then drops as the body's immune system launches an orchestrated fight.

More persistent or severe symptoms may not surface for several years, even a decade or more, after HIV first enters the body in adults, or within two years in children born with the virus. This period of "asymptomatic" infection varies from individual to individual. Some people may begin to have symptoms as soon as a few months, while others may be symptom-free for more than 10 years. However, during the "asymptomatic" period, the virus will be actively multiplying, infecting, and killing cells of the immune system.

Latency stage

A strong immune defense reduces the number of viral particles in the blood stream, marking the start of the infection's clinical latency stage. Clinical latency can vary between two weeks and 20 years. During this early phase of infection, HIV is active within lymphoid organs, where large amounts of virus become trapped in the follicular dendritic cells (FDC) network.[69] The surrounding tissues that are rich in CD4+ T cells may also become infected, and viral particles accumulate both in infected cells and as free virus. Individuals who are in this phase are still infectious. During this time, CD4+ CD45RO+ T cells carry most of the proviral load.

Acute HIV infection

The initial infection with HIV generally occurs after transfer of body fluids from an infected person to an uninfected one. The first stage of infection, the primary, or acute infection, is a period of rapid viral replication that immediately follows the individual's exposure to HIV leading to an abundance of virus in the peripheral blood with levels of HIV commonly approaching several million viruses per mL. This response is accompanied by a marked drop in the numbers of circulating CD4+ T cells. This acute viremia is associated in virtually all patients with the activation of CD8+ T cells, which kill HIV-infected cells, and subsequently with antibody production, or seroconversion. The CD8+ T cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4+ T cell counts rebound to around 800 cells per mL (the normal blood value is 1200 cells per mL ). A good CD8+ T cell response has been linked to slower disease progression and a better prognosis, though it does not eliminate the virus. During this period (usually 2-4 weeks post-exposure) most individuals (80 to 90%) develop an influenza or mononucleosis-like illness called acute HIV infection, the most common symptoms of which may include fever, lymphadenopathy, pharyngitis, rash, myalgia, malaise, mouth and esophagal sores, and may also include, but less commonly, headache, nausea and vomiting, enlarged liver/spleen, weight loss, thrush, and neurological symptoms. Infected individuals may experience all, some, or none of these symptoms. The duration of symptoms varies, averaging 28 days and usually lasting at least a week. Because of the nonspecific nature of these symptoms, they are often not recognized as signs of HIV infection. Even if patients go to their doctors or a hospital, they will often be misdiagnosed as having one of the more common infectious diseases with the same symptoms. Consequently, these primary symptoms are not used to diagnose HIV infection as they do not develop in all cases and because many are caused by other more common diseases. However, recognizing the syndrome can be important because the patient is much more infectious during this period.

Acute HIV infection

The initial infection with HIV generally occurs after transfer of body fluids from an infected person to an uninfected one. The first stage of infection, the primary, or acute infection, is a period of rapid viral replication that immediately follows the individual's exposure to HIV leading to an abundance of virus in the peripheral blood with levels of HIV commonly approaching several million viruses per mL. This response is accompanied by a marked drop in the numbers of circulating CD4+ T cells. This acute viremia is associated in virtually all patients with the activation of CD8+ T cells, which kill HIV-infected cells, and subsequently with antibody production, or seroconversion. The CD8+ T cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4+ T cell counts rebound to around 800 cells per mL (the normal blood value is 1200 cells per mL ). A good CD8+ T cell response has been linked to slower disease progression and a better prognosis, though it does not eliminate the virus. During this period (usually 2-4 weeks post-exposure) most individuals (80 to 90%) develop an influenza or mononucleosis-like illness called acute HIV infection, the most common symptoms of which may include fever, lymphadenopathy, pharyngitis, rash, myalgia, malaise, mouth and esophagal sores, and may also include, but less commonly, headache, nausea and vomiting, enlarged liver/spleen, weight loss, thrush, and neurological symptoms. Infected individuals may experience all, some, or none of these symptoms. The duration of symptoms varies, averaging 28 days and usually lasting at least a week. Because of the nonspecific nature of these symptoms, they are often not recognized as signs of HIV infection. Even if patients go to their doctors or a hospital, they will often be misdiagnosed as having one of the more common infectious diseases with the same symptoms. Consequently, these primary symptoms are not used to diagnose HIV infection as they do not develop in all cases and because many are caused by other more common diseases. However, recognizing the syndrome can be important because the patient is much more infectious during this period.

Genetic variability

HIV differs from many viruses in that it has very high genetic variability. This diversity is a result of its fast replication cycle, with the generation of 109 to 1010 virions every day, coupled with a high mutation rate of approximately 3 x 10-5 per nucleotide base per cycle of replication and recombinogenic properties of reverse transcriptase.This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day

Assembly and release

The final step of the viral cycle, assembly of new HIV-1 virons, begins at the plasma membrane of the host cell. The Env polyprotein (gp160) goes through the endoplasmic reticulum and is transported to the Golgi complex where it is cleaved by protease and processed into the two HIV envelope glycoproteins gp41 and gp120. These are transported to the plasma membrane of the host cell where gp41 anchors the gp120 to the membrane of the infected cell. The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell. Maturation either occurs in the forming bud or in the immature virion after it buds from the host cell. During maturation, HIV proteases cleave the polyproteins into individual functional HIV proteins and enzymes. The various structural components then assemble to produce a mature HIV virion. This cleavage step can be inhibited by protease inhibitors. The mature virus is then able to infect another cell.

Replication and transcription

Once the viral capsid enters the cell, an enzyme called reverse transcriptase liberates the single-stranded (+)RNA from the attached viral proteins and copies it into a complementary DNA.[52] This process of reverse transcription is extremely error-prone and it is during this step that mutations may occur. Such mutations may cause drug resistance. The reverse transcriptase then makes a complementary DNA strand to form a double-stranded viral DNA intermediate (vDNA). This vDNA is then transported into the cell nucleus. The integration of the viral DNA into the host cell's genome is carried out by another viral enzyme called integrase

Replication cycle

HIV enters macrophages and CD4+ T cells by the adsorption of glycoproteins on its surface to receptors on the target cell followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.[48][49]
Entry to the cell begins through interaction of the trimeric envelope complex (gp160 spike) and both CD4 and a chemokine receptor (generally either CCR5 or CXCR4, but others are known to interact) on the cell surface. gp120 binds to integrin α4β7 activating LFA-1 the central integrin involved in the establishment of virological synapses, which facilitate efficient cell-to-cell spreading of HIV-1.The gp160 spike contains binding domains for both CD4 and chemokine receptors. The first step in fusion involves the high-affinity attachment of the CD4 binding domains of gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine binding domains of gp120 and allowing them to interact with the target chemokine receptor. This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane. Repeat sequences in gp41, HR1 and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.
Once HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease and protease, are injected into the cell.During the microtubule based transport to the nucleus, the viral single strand RNA genome is transcribed into double strand DNA, which is then integrated into a host chromosome.
HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using mannose-specific C-type lectin receptors such as DC-SIGN can also be used. DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T cells once the virus has been captured in the mucosa by DCs.

Treatment

There is currently no vaccine or cure for HIV or AIDS. The only known method of prevention is avoiding exposure to the virus. However, an antiretroviral treatment, known as post-exposure prophylaxis, is believed to reduce the risk of infection if begun directly after exposure. Current treatment for HIV infection consists of highly active antiretroviral therapy, or HAART. This has been highly beneficial to many HIV-infected individuals since its introduction in 1996, when the protease inhibitor-based HAART initially became available. Current HAART options are combinations (or "cocktails") consisting of at least three drugs belonging to at least two types, or "classes," of antiretroviral agents. Typically, these classes are two nucleoside analogue reverse transcriptase inhibitors (NARTIs or NRTIs) plus either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI). Because AIDS progression in children is more rapid and less predictable than in adults, particularly in young infants, more aggressive treatment is recommended for children than adults. In developed countries where HAART is available, doctors assess their patients thoroughly: measuring the viral load, how fast CD4 declines, and patient readiness. They then decide when to recommend starting treatment.
HAART allows the stabilisation of the patient’s symptoms and viremia, but it neither cures the patient, nor alleviates the symptoms; high levels of HIV-1, often HAART resistant, return once treatment is stopped. Moreover, it would take more than a lifetime for HIV infection to be cleared using HAART.Despite this, many HIV-infected individuals have experienced remarkable improvements in their general health and quality of life, which has led to a large reduction in HIV-associated morbidity and mortality in the developed world. The average life expectancy of an HIV infected individual is 32 years from the time of infection if treatment is started when the CD4 count is 350/µL. The study predicting this was, however, limited as it did not take into account possible future treatments and the projection has not been confirmed within a clinical cohort setting. In the absence of HAART, progression from HIV infection to AIDS has been observed to occur at a median of between nine to ten years and the median survival time after developing AIDS is only 9.2 months.

However, HAART sometimes achieves far less than optimal results, in some circumstances being effective in less than fifty percent of patients. This is due to a variety of reasons such as medication intolerance/side effects, prior ineffective antiretroviral therapy and infection with a drug-resistant strain of HIV. However, non-adherence and non-persistence with antiretroviral therapy is the major reason most individuals fail to benefit from HAART.The reasons for non-adherence and non-persistence with HAART are varied and overlapping. Major psychosocial issues, such as poor access to medical care, inadequate social supports, psychiatric disease and drug abuse contribute to non-adherence. The complexity of these HAART regimens, whether due to pill number, dosing frequency, meal restrictions or other issues along with side effects that create intentional non-adherence also contribute to this problem. The side effects include lipodystrophy, dyslipidemia, insulin resistance, an increase in cardiovascular risks and birth defects.
The timing for starting HIV treatment is still debated. There is no question that treatment should be started before the patient's CD4 count falls below 200, and most national guidelines say to start treatment once the CD4 count falls below 350; but there is some evidence from cohort studies that treatment should be started before the CD4 count falls below 350.

There is also evidence to say that treatment should be started before CD4 count falls below 180. In those countries where CD4 counts are not available, patients with WHO stage III or IV disease should be offered treatment.
Anti-retroviral drugs are expensive, and the majority of the world's infected individuals do not have access to medications and treatments for HIV and AIDS. Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance. Unfortunately, only a vaccine is thought to be able to halt the pandemic. This is because a vaccine would cost less, thus being affordable for developing countries, and would not require daily treatment. However, after over 20 years of research, HIV-1 remains a difficult target for a vaccine. A region on HIV's surface is a potential target for a vaccine.
Promising new treatments include Cre recombinase and the enzyme Tre recombinase both or which are able to remove HIV from an infected cell. These enzymes promise a treatment in which a patient's stem cells are extracted, cured, and reinjected to promulgate the enzyme into the body. The carried enzyme then finds and removes the virus.

Transmission

Since the beginning of the pandemic, three main transmission routes for HIV have been identified:-

(1)Sexual route

The majority of HIV infections are acquired through unprotected sexual relations. Sexual transmission can occur when infected sexual secretions of one partner come into contact with the genital, oral, or rectal mucous membranes of another.

(2)Blood or blood product route

This transmission route can account for infections in intravenous drug users, hemophiliacs and recipients of blood transfusions (though most transfusions are checked for HIV in the developed world) and blood products. It is also of concern for persons receiving medical care in regions where there is prevalent substandard hygiene in the use of injection equipment, such as the reuse of needles in Third World countries. HIV can also be spread through the sharing of needles. Health care workers such as nurses, laboratory workers, and doctors, have also been infected, although this occurs more rarely. People who give and receive tattoos, piercings, and scarification procedures can also be at risk of infection.

(3)Mother-to-child transmission (MTCT)

The transmission of the virus from the mother to the child can occur in utero during pregnancy and intrapartum at childbirth. In the absence of treatment, the transmission rate between the mother and child is around 25%.[15] However, where combination antiretroviral drug treatment and Cesarian section are available, this risk can be reduced to as low as 1%.[15] Breast feeding also presents a risk of infection for the baby.

HIV

Human immunodeficiency virus (HIV) is a retrovirus that can lead to acquired immunodeficiency syndrome (AIDS), a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections. Previous names for the virus include human T-lymphotropic virus-III (HTLV-III), lymphadenopathy-associated virus (LAV), and AIDS-associated retrovirus (ARV).